Impact of Vitamin D Therapy in treating
X-linked hypophosphatemic rickets
Kate Barratt
Research Proposal
For the degree of Masters by Research (Medical Science)
Supervisors
Associate Professor Paul Anderson
Professor Gerald Atkins
Professor Howard Morris

OUTLINE:
X-Linked Hypophosphatemic Rickets (XLH) is a rare hereditary disorder that is difficult to treat without significant side-effects ADDIN EN.CITE <EndNote><Cite><Author>Lee</Author><Year>2013</Year><RecNum>49</RecNum><DisplayText>(Lee &amp; Imel 2013)</DisplayText><record><rec-number>49</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1523104063″>49</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Lee, J. Y</author><author>Imel, E. A</author></authors></contributors><titles><title>The Changing Face of Hypophosphatemic Disorders in the FGF-23 Era</title><secondary-title>Paediatr Endocrinol Rev.</secondary-title></titles><periodical><full-title>Paediatr Endocrinol Rev.</full-title></periodical><pages>367-379</pages><volume>10</volume><dates><year>2013</year></dates><urls></urls></record></Cite></EndNote>(Lee & Imel 2013). XLH is caused by a mutation in the osteocyte gene, phosphate-regulating endopeptidase homolog, X-linked (PHEX) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW5nbGFydDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW5nbGFydDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE.DATA (Linglart et al. 2014). This mutation of PHEX impairs cleavage, and accumulation, of Fibroblast Growth Factor 23 (FGF23) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdXJhbGk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS
ZWNOdW0+NjwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oTXVyYWxpIGV0IGFsLiAyMDE2KTwvRGlzcGxh
eVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj42PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl
eSBhcHA9IkVOIiBkYi1pZD0ieGZ3ZnhzOXYyenJwZTllcjJhOXB3ZDlmeHY1ejJ2OTJ3ZTVkIiB0
aW1lc3RhbXA9IjE1MTk3OTE4MTQiPjY8L2tleT48a2V5IGFwcD0iRU5XZWIiIGRiLWlkPSIiPjA8
L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv
cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk11cmFsaSwgUy4gSy48L2F1
dGhvcj48YXV0aG9yPkFuZHJ1a2hvdmEsIE8uPC9hdXRob3I+PGF1dGhvcj5DbGlua2VuYmVhcmQs
IEUuIEwuPC9hdXRob3I+PGF1dGhvcj5XaGl0ZSwgSy4gRS48L2F1dGhvcj48YXV0aG9yPkVyYmVu
LCBSLiBHLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRl
cGFydG1lbnQgb2YgQmlvbWVkaWNhbCBTY2llbmNlcywgVW5pdmVyc2l0eSBvZiBWZXRlcmluYXJ5
IE1lZGljaW5lLCBWaWVubmEsIEF1c3RyaWEuJiN4RDtEZXBhcnRtZW50IG9mIE1lZGljYWwgYW5k
IE1vbGVjdWxhciBHZW5ldGljcywgSW5kaWFuYSBVbml2ZXJzaXR5IFNjaG9vbCBvZiBNZWRpY2lu
ZSwgSW5kaWFuYXBvbGlzLCBJbmRpYW5hLCBVbml0ZWQgU3RhdGVzIG9mIEFtZXJpY2EuPC9hdXRo
LWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+RXhjZXNzaXZlIE9zdGVvY3l0aWMgRmdmMjMgU2VjcmV0
aW9uIENvbnRyaWJ1dGVzIHRvIFB5cm9waG9zcGhhdGUgQWNjdW11bGF0aW9uIGFuZCBNaW5lcmFs
aXphdGlvbiBEZWZlY3QgaW4gSHlwIE1pY2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UExvUyBC
aW9sPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UExv
UyBCaW9sPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+ZTEwMDI0Mjc8L3BhZ2VzPjx2
b2x1bWU+MTQ8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWxr
YWxpbmUgUGhvc3BoYXRhc2UvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5
d29yZD48a2V5d29yZD5Cb25lIGFuZCBCb25lcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3Jk
PipDYWxjaWZpY2F0aW9uLCBQaHlzaW9sb2dpYzwva2V5d29yZD48a2V5d29yZD5EaXBob3NwaGF0
ZXMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RmFtaWxpYWwgSHlwb3Bob3NwaGF0ZW1p
YyBSaWNrZXRzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkZpYnJvYmxhc3QgR3Jvd3Ro
IEZhY3RvcnMvZ2VuZXRpY3MvbWV0YWJvbGlzbS8qc2VjcmV0aW9uPC9rZXl3b3JkPjxrZXl3b3Jk
Pk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+T3N0ZW9jeXRlcy8qc2VjcmV0aW9uPC9rZXl3b3JkPjxr
ZXl3b3JkPlJOQSwgTWVzc2VuZ2VyL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UmVjZXB0
b3IsIEZpYnJvYmxhc3QgR3Jvd3RoIEZhY3RvciwgVHlwZSAzL2dlbmV0aWNzPC9rZXl3b3JkPjxr
ZXl3b3JkPlZpdGFtaW4gRCBEZWZpY2llbmN5L2Jsb29kPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh
dGVzPjx5ZWFyPjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHI8L2RhdGU+PC9wdWItZGF0
ZXM+PC9kYXRlcz48aXNibj4xNTQ1LTc4ODUgKEVsZWN0cm9uaWMpJiN4RDsxNTQ0LTkxNzMgKExp
bmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3MDM1NjM2PC9hY2Nlc3Npb24tbnVtPjx1cmxz
PjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8y
NzAzNTYzNjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0ODE4MDIwPC9j
dXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMzcxL2pvdXJuYWwucGJpby4xMDAy
NDI3PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdXJhbGk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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=
ADDIN EN.CITE.DATA (Murali et al. 2016). Elevated FGF23 levels in XLH causes excessive renal excretion of phosphate leading to hypophosphatemia, and low circulating active vitamin D (1,25(OH)2D) levels due to both inhibited synthesis and excessive catabolism of vitamin D ADDIN EN.CITE <EndNote><Cite><Author>Tenenhouse</Author><Year>1990</Year><RecNum>55</RecNum><DisplayText>(Tenenhouse &amp; Jones 1990)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533031688″>55</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Tenenhouse, H. S</author><author>Jones, G.</author></authors></contributors><titles><title>Abnormal Regulation of Renal Vitamin D Catabolism by Dietary Phosphate in Murine X-linked Hypophosphatemic Rickets</title><secondary-title>J Clin. Invest.</secondary-title></titles><periodical><full-title>J Clin. Invest.</full-title></periodical><pages>1450-1455</pages><volume>85</volume><dates><year>1990</year></dates><urls></urls></record></Cite></EndNote>(Tenenhouse & Jones 1990). It has been long thought that disturbed renal metabolism of vitamin D is major contributor to the development of undermineralised bone, or rickets ADDIN EN.CITE <EndNote><Cite><Author>Tenenhouse</Author><Year>1990</Year><RecNum>55</RecNum><DisplayText>(Tenenhouse &amp; Jones 1990)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533031688″>55</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Tenenhouse, H. S</author><author>Jones, G.</author></authors></contributors><titles><title>Abnormal Regulation of Renal Vitamin D Catabolism by Dietary Phosphate in Murine X-linked Hypophosphatemic Rickets</title><secondary-title>J Clin. Invest.</secondary-title></titles><periodical><full-title>J Clin. Invest.</full-title></periodical><pages>1450-1455</pages><volume>85</volume><dates><year>1990</year></dates><urls></urls></record></Cite></EndNote>(Tenenhouse & Jones 1990). However, recent evidence suggests that (a) local metabolism of 1,25(OH)2D in bone has an independent and critical role for bone mineralisation ADDIN EN.CITE <EndNote><Cite><Author>Anderson</Author><Year>2017</Year><RecNum>94</RecNum><DisplayText>(Anderson 2017)</DisplayText><record><rec-number>94</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1534470997″>94</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Anderson, P. H.</author></authors></contributors><auth-address>Musculoskeletal Biology Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, 5001, Australia. [email protected]</auth-address><titles><title>Vitamin D Activity and Metabolism in Bone</title><secondary-title>Curr Osteoporos Rep</secondary-title></titles><periodical><full-title>Curr Osteoporos Rep</full-title></periodical><pages>443-449</pages><volume>15</volume><number>5</number><edition>2017/08/16</edition><keywords><keyword>25-Hydroxyvitamin D3 1-alpha-Hydroxylase/*metabolism</keyword><keyword>Autocrine Communication</keyword><keyword>Bone Resorption/metabolism</keyword><keyword>Bone and Bones/*metabolism</keyword><keyword>Calcification, Physiologic/physiology</keyword><keyword>Fracture Healing/physiology</keyword><keyword>Humans</keyword><keyword>Receptors, Calcitriol/*metabolism</keyword><keyword>Vitamin D/*analogs &amp; derivatives/metabolism</keyword><keyword>Vitamin D3 24-Hydroxylase/*metabolism</keyword><keyword>Cyp24a1</keyword><keyword>Cyp27b1</keyword><keyword>Mineralisation</keyword><keyword>Osteoblasts</keyword><keyword>Vitamin D</keyword><keyword>Vitamin D receptor</keyword></keywords><dates><year>2017</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1544-2241 (Electronic) 1544-1873 (Linking)</isbn><accession-num>28808890</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/28808890</url></related-urls></urls><electronic-resource-num>10.1007/s11914-017-0394-8</electronic-resource-num></record></Cite></EndNote>(Anderson 2017) (b) that the inhibition of vitamin D catabolism in disorders of rickets due to FGF23 excess, induces the near-complete healing of rickets without the need to lower FGF23 levels nor rescue the hypophosphatemia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Bai et al. 2016). These data, and the importance of finding effective treatments for XLH provide great importance for investigating the following hypothesis and aims:
Hypothesis: Raising active vitamin D (1,25D) levels within the bone and/or the intestine (via preventing catabolism) prevents rickets in the Hyp mouse model (the mouse homolog for the disorder of XLH) by increasing mineralisation.

We Will Write a Custom Essay Specifically
For You For Only $13.90/page!


order now

Aim 1: To determine whether raising circulating 25-hydroxyvitamin D (25D) levels heal the bone in Hyp mice.

Aim 2: To determine whether raising osteocyte levels of active vitamin D (1,25(OH)2D) heals the bone of Hyp mice.

LITERATURE REVIEW:
416623574295Figure 1: Bone deformities in a severe case of XLH
0Figure 1: Bone deformities in a severe case of XLH
Prevalence and impact of X-linked Hypophosphatemic Rickets: X-Linked Hypophosphatemia (XLH) is a rare genetic disorder, affecting 1 in 20,000 individuals PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BemFtPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj
TnVtPjkwPC9SZWNOdW0+PERpc3BsYXlUZXh0PihBemFtIGV0IGFsLiAyMDAzKTwvRGlzcGxheVRl
eHQ+PHJlY29yZD48cmVjLW51bWJlcj45MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg
YXBwPSJFTiIgZGItaWQ9Inhmd2Z4czl2MnpycGU5ZXIyYTlwd2Q5Znh2NXoydjkyd2U1ZCIgdGlt
ZXN0YW1wPSIxNTM0MDY5MDkxIj45MDwva2V5PjxrZXkgYXBwPSJFTldlYiIgZGItaWQ9IiI+MDwv
a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y
ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QXphbSwgTi48L2F1dGhvcj48
YXV0aG9yPlpoYW5nLCBNLiBZLjwvYXV0aG9yPjxhdXRob3I+V2FuZywgWC48L2F1dGhvcj48YXV0
aG9yPlRlbmVuaG91c2UsIEguIFMuPC9hdXRob3I+PGF1dGhvcj5Qb3J0YWxlLCBBLiBBLjwvYXV0
aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2Yg
UGVkaWF0cmljcywgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlhIFNhbiBGcmFuY2lzY28sIFNhbiBG
cmFuY2lzY28sIENhbGlmb3JuaWEgOTQxNDMsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0
aXRsZT5EaXNvcmRlcmVkIHJlZ3VsYXRpb24gb2YgcmVuYWwgMjUtaHlkcm94eXZpdGFtaW4gRC0x
YWxwaGEtaHlkcm94eWxhc2UgZ2VuZSBleHByZXNzaW9uIGJ5IHBob3NwaG9ydXMgaW4gWC1saW5r
ZWQgaHlwb3Bob3NwaGF0ZW1pYyAoaHlwKSBtaWNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkVu
ZG9jcmlub2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10
aXRsZT5FbmRvY3Jpbm9sb2d5PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzQ2My04
PC9wYWdlcz48dm9sdW1lPjE0NDwvdm9sdW1lPjxudW1iZXI+ODwvbnVtYmVyPjxlZGl0aW9uPjIw
MDMvMDcvMTc8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjI1LUh5ZHJveHl2aXRhbWluIEQz
IDEtYWxwaGEtSHlkcm94eWxhc2UvKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8
L2tleXdvcmQ+PGtleXdvcmQ+Q3l0b2Nocm9tZSBQLTQ1MCBFbnp5bWUgU3lzdGVtL2dlbmV0aWNz
PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Np
b24gUmVndWxhdGlvbiwgRW56eW1vbG9naWMvKmRydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29y
ZD5HZW5ldGljIExpbmthZ2U8L2tleXdvcmQ+PGtleXdvcmQ+SHlwb3Bob3NwaGF0ZW1pYSwgRmFt
aWxpYWwvKmVuenltb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+S2lkbmV5Lyplbnp5bW9sb2d5PC9r
ZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5
d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+UGhvc3Bob3J1cy9ibG9v
ZC8qcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaG9ydXMsIERpZXRhcnkvYWRt
aW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlPC9rZXl3b3JkPjxrZXl3b3JkPlJOQSwgTWVzc2VuZ2Vy
L2FuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPlN0ZXJvaWQgSHlkcm94eWxhc2VzL2dlbmV0aWNz
PC9rZXl3b3JkPjxrZXl3b3JkPlZpdGFtaW4gRDMgMjQtSHlkcm94eWxhc2U8L2tleXdvcmQ+PGtl
eXdvcmQ+WCBDaHJvbW9zb21lPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDM8
L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNi
bj4wMDEzLTcyMjcgKFByaW50KSYjeEQ7MDAxMy03MjI3IChMaW5raW5nKTwvaXNibj48YWNjZXNz
aW9uLW51bT4xMjg2NTMyNjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+
aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTI4NjUzMjY8L3VybD48L3JlbGF0
ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEyMTAvZW4uMjAwMy0w
MjU1PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BemFtPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj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==
ADDIN EN.CITE.DATA (Azam et al. 2003). The disease is characterised by the excessive renal excretion of serum phosphate leading to hypophosphatemia ADDIN EN.CITE <EndNote><Cite><Author>Saito</Author><Year>2009</Year><RecNum>28</RecNum><DisplayText>(Saito &amp; Fukumoto 2009)</DisplayText><record><rec-number>28</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519884606″>28</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Saito, T.</author><author>Fukumoto, S.</author></authors></contributors><auth-address>Department of Pediatrics, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.</auth-address><titles><title>Fibroblast Growth Factor 23 (FGF23) and Disorders of Phosphate Metabolism</title><secondary-title>Int J Pediatr Endocrinol</secondary-title></titles><periodical><full-title>Int J Pediatr Endocrinol</full-title></periodical><pages>496514</pages><volume>2009</volume><dates><year>2009</year></dates><isbn>1687-9856 (Electronic) 1687-9848 (Linking)</isbn><accession-num>19956747</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/19956747</url></related-urls></urls><custom2>PMC2775677</custom2><electronic-resource-num>10.1155/2009/496514</electronic-resource-num></record></Cite></EndNote>(Saito & Fukumoto 2009). Hypophosphatemia is generally considered to result in reduced hydroxyapatite (bone mineral) formation resulting in under-mineralisation of the skeleton or rickets (Figure 1) ADDIN EN.CITE <EndNote><Cite><Author>De Menezes Filho</Author><Year>2006</Year><RecNum>101</RecNum><DisplayText>(De Menezes Filho, De Castro &amp; Damiani 2006)</DisplayText><record><rec-number>101</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1537168877″>101</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>De Menezes Filho, H.</author><author>De Castro, L. C. G.</author><author>Damiani, D.</author></authors></contributors><titles><title>Hypophosphatemic Rickets and Osteomalacia</title></titles><volume>50</volume><number>4</number><dates><year>2006</year></dates><urls></urls></record></Cite></EndNote>(De Menezes Filho, De Castro & Damiani 2006). XLH usually presents in late infancy as growth retardation, skeletal deformities and rickets become apparent. XLH children display a delay in walking, bowed legs, craniostenosis, dental abscesses, entesopathy, fractures, and bone pain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWtpdGllPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWtpdGllPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48
UmVjTnVtPjIyPC9SZWNOdW0+PERpc3BsYXlUZXh0PihMaW5nbGFydCBldCBhbC4gMjAxNDsgTWFr
aXRpZSBldCBhbC4gMjAwMyk8L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjI8L3Jl
Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ4ZndmeHM5djJ6cnBl
OWVyMmE5cHdkOWZ4djV6MnY5MndlNWQiIHRpbWVzdGFtcD0iMTUxOTc5NDI4NSI+MjI8L2tleT48
a2V5IGFwcD0iRU5XZWIiIGRiLWlkPSIiPjA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUg
bmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9y
cz48YXV0aG9yPk1ha2l0aWUsIE8uPC9hdXRob3I+PGF1dGhvcj5Eb3JpYSwgQS48L2F1dGhvcj48
YXV0aG9yPktvb2gsIFMuIFcuPC9hdXRob3I+PGF1dGhvcj5Db2xlLCBXLiBHLjwvYXV0aG9yPjxh
dXRob3I+RGFuZW1hbiwgQS48L2F1dGhvcj48YXV0aG9yPlNvY2hldHQsIEUuPC9hdXRob3I+PC9h
dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGl2aXNpb24gb2YgRW5kb2NyaW5v
bG9neSwgVGhlIEhvc3BpdGFsIGZvciBTaWNrIENoaWxkcmVuLCBVbml2ZXJzaXR5IG9mIFRvcm9u
dG8sIFRvcm9udG8sIE9udGFyaW8sIENhbmFkYSBNNUcgMVg4LiBvdXRpLm1ha2l0aWVAaGVsc2lu
a2kuZmk8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5FYXJseSB0cmVhdG1lbnQgaW1wcm92
ZXMgZ3Jvd3RoIGFuZCBiaW9jaGVtaWNhbCBhbmQgcmFkaW9ncmFwaGljIG91dGNvbWUgaW4gWC1s
aW5rZWQgaHlwb3Bob3NwaGF0ZW1pYyByaWNrZXRzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkog
Q2xpbiBFbmRvY3Jpbm9sIE1ldGFiPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj
YWw+PGZ1bGwtdGl0bGU+SiBDbGluIEVuZG9jcmlub2wgTWV0YWI8L2Z1bGwtdGl0bGU+PC9wZXJp
b2RpY2FsPjxwYWdlcz4zNTkxLTc8L3BhZ2VzPjx2b2x1bWU+ODg8L3ZvbHVtZT48bnVtYmVyPjg8
L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWdlIG9mIE9uc2V0PC9rZXl3b3JkPjxrZXl3b3Jk
PkJvZHkgSGVpZ2h0L2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5Cb25lIGFuZCBCb25l
cy9kaWFnbm9zdGljIGltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+Q2FsY2l0cmlvbC9ibG9vZDwv
a2V5d29yZD48a2V5d29yZD5DaGlsZDwva2V5d29yZD48a2V5d29yZD5DaGlsZCwgUHJlc2Nob29s
PC9rZXl3b3JkPjxrZXl3b3JkPkdyb3d0aC8qZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3Jk
Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeXBvcGhvc3BoYXRlbWlhL2Jsb29kPC9rZXl3b3Jk
PjxrZXl3b3JkPkh5cG9waG9zcGhhdGVtaWEsIEZhbWlsaWFsL2RpYWdub3N0aWMgaW1hZ2luZy9t
ZXRhYm9saXNtLyp0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkluZmFudDwva2V5d29yZD48a2V5
d29yZD5SYWRpb2dyYXBoeTwva2V5d29yZD48a2V5d29yZD5SZXRyb3NwZWN0aXZlIFN0dWRpZXM8
L2tleXdvcmQ+PGtleXdvcmQ+VHJlYXRtZW50IE91dGNvbWU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48
ZGF0ZXM+PHllYXI+MjAwMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkF1ZzwvZGF0ZT48L3B1Yi1k
YXRlcz48L2RhdGVzPjxpc2JuPjAwMjEtOTcyWCAoUHJpbnQpJiN4RDswMDIxLTk3MlggKExpbmtp
bmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjEyOTE1NjQxPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxy
ZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xMjkx
NTY0MTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+
MTAuMTIxMC9qYy4yMDAzLTAzMDAzNjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+
PC9DaXRlPjxDaXRlPjxBdXRob3I+TGluZ2xhcnQ8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS
ZWNOdW0+ODk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjg5PC9yZWMtbnVtYmVyPjxmb3Jl
aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0ieGZ3ZnhzOXYyenJwZTllcjJhOXB3ZDlmeHY1
ejJ2OTJ3ZTVkIiB0aW1lc3RhbXA9IjE1MzM1Mjc5NTUiPjg5PC9rZXk+PGtleSBhcHA9IkVOV2Vi
IiBkYi1pZD0iIj4wPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwg
QXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5MaW5n
bGFydCwgQS48L2F1dGhvcj48YXV0aG9yPkJpb3NzZS1EdXBsYW4sIE0uPC9hdXRob3I+PGF1dGhv
cj5CcmlvdCwgSy48L2F1dGhvcj48YXV0aG9yPkNoYXVzc2FpbiwgQy48L2F1dGhvcj48YXV0aG9y
PkVzdGVybGUsIEwuPC9hdXRob3I+PGF1dGhvcj5HdWlsbGF1bWUtQ3ppdHJvbSwgUy48L2F1dGhv
cj48YXV0aG9yPkthbWVuaWNreSwgUC48L2F1dGhvcj48YXV0aG9yPk5ldm91eCwgSi48L2F1dGhv
cj48YXV0aG9yPlByaWUsIEQuPC9hdXRob3I+PGF1dGhvcj5Sb3RoZW5idWhsZXIsIEEuPC9hdXRo
b3I+PGF1dGhvcj5XaWNhcnQsIFAuPC9hdXRob3I+PGF1dGhvcj5IYXJ2ZW5ndCwgUC48L2F1dGhv
cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5TZXJ2aWNlIGQmYXBvcztF
bmRvY3Jpbm9sb2dpZSBldCBEaWFiZXRvbG9naWUgZGUgbCZhcG9zO0VuZmFudCBTZXJ2aWNlIGRl
IFBlZGlhdHJpZSBnZW5lcmFsZSAtIENvbnN1bHRhdGlvbiBkZSByaHVtYXRvbG9naWUgU2Vydmlj
ZSBkJmFwb3M7RW5kb2NyaW5vbG9naWUgZXQgZGVzIE1hbGFkaWVzIGRlIGxhIFJlcHJvZHVjdGlv
biBTZXJ2aWNlIGQmYXBvcztPUkwgZXQgY2hpcnVyZ2llIGNlcnZpY28tbWF4aWxsby1mYWNpYWxl
SG9waXRhbCBCaWNldHJlLCBBUEhQLCA3OCBydWUgZHUgR2VuZXJhbCBMZWNsZXJjLCA5NDI3MCBM
ZSBLcmVtbGluIEJpY2V0cmUsIEZyYW5jZSBVbml2ZXJzaXRlIFBhcmlzIDExRmFjdWx0ZSBkZSBN
ZWRlY2luZSwgSG9waXRhbCBCaWNldHJlLCA3MCBydWUgZHUgR2VuZXJhbCBMZWNsZXJjLCA5NDI3
MCBMZSBLcmVtbGluLUJpY2V0cmUsIEZyYW5jZSBDZW50cmUgZGUgUmVmZXJlbmNlIGRlcyBNYWxh
ZGllcyBSYXJlcyBkdSBNZXRhYm9saXNtZSBkdSBDYWxjaXVtIGV0IGR1IFBob3NwaG9yZUxlIEty
ZW1saW4tQmljZXRyZSwgRnJhbmNlIFNlcnZpY2UgZCZhcG9zO09kb250b2xvZ2llLU1hbGFkaWVz
IFJhcmVzIEhvcGl0YWwgQnJldG9ubmVhdSAyIHJ1ZSBDYXJwZWF1eDc1MDE4IFBhcmlzLCBGcmFu
Y2UgVW5pdmVyc2l0ZSBQYXJpcyBEZXNjYXJ0ZXMgMTIgUnVlIGRlIGwmYXBvcztFY29sZSBkZSBN
ZWRlY2luZTc1MDA2IFBhcmlzLCBGcmFuY2UgU2VydmljZSBSaHVtYXRvbG9naWUgQiBIb3BpdGFs
IENvY2hpbkFQSFAsIDI3LCBydWUgZHUgRmF1Ym91cmcgU2FpbnQtSmFjcXVlcywgNzUwMTQgUGFy
aXMsIEZyYW5jZSBDZW50cmUgZGUgUmVmZXJlbmNlIGRlcyBNYWxhZGllcyBSYXJlcyBkZXMgTWFs
YWRpZXMgQXV0by1JbmZsYW1tYXRvaXJlcyBSYXJlcyBkZSBsJmFwb3M7RW5mYW50TGUgS3JlbWxp
biBCaWNldHJlLCBGcmFuY2UgU2VydmljZSBkJmFwb3M7ZXhwbG9yYXRpb25zIGZvbmN0aW9ubmVs
bGVzIHJlbmFsZXMgU2VydmljZSBkZSBDaGlydXJnaWUgaW5mYW50aWxlIG9ydGhvcGVkaXF1ZUhv
cGl0YWwgTmVja2VyLUVuZmFudHMgTWFsYWRlcywgMTQ5IHJ1ZSBkZSBTZXZyZXMsIDc1MDE1IFBh
cmlzLCBGcmFuY2UgQXNzb2NpYXRpb24gZGUgcGF0aWVudHMgUlZSSC1YTEgyMCBydWUgTWVybGlu
IGRlIFRoaW9udmlsbGUsIDkyMTUwIFN1cmVzbmVzLCBGcmFuY2UuPC9hdXRoLWFkZHJlc3M+PHRp
dGxlcz48dGl0bGU+VGhlcmFwZXV0aWMgbWFuYWdlbWVudCBvZiBoeXBvcGhvc3BoYXRlbWljIHJp
Y2tldHMgZnJvbSBpbmZhbmN5IHRvIGFkdWx0aG9vZDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5F
bmRvY3IgQ29ubmVjdDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxs
LXRpdGxlPkVuZG9jciBDb25uZWN0PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+UjEz
LTMwPC9wYWdlcz48dm9sdW1lPjM8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4y
MDE0LzAyLzIwPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5YLWxpbmtlZCBoeXBvcGhvc3Bo
YXRlbWljIHJpY2tldHM8L2tleXdvcmQ+PGtleXdvcmQ+Ym9uZTwva2V5d29yZD48a2V5d29yZD5j
YWxjaXVtPC9rZXl3b3JkPjxrZXl3b3JkPnJhcmUgZGlzZWFzZXMvc3luZHJvbWVzPC9rZXl3b3Jk
Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PC9kYXRlcz48aXNibj4yMDQ5LTM2
MTQgKFByaW50KSYjeEQ7MjA0OS0zNjE0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4y
NDU1MDMyMjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93
d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQ1NTAzMjI8L3VybD48L3JlbGF0ZWQtdXJscz48
L3VybHM+PGN1c3RvbTI+UE1DMzk1OTczMDwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1u
dW0+MTAuMTUzMC9FQy0xMy0wMTAzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48
L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE.DATA (Linglart et al. 2014; Makitie et al. 2003). The principal symptoms of XLH in adults are bone pain, joint pain, and stiffness. As patients age, long-term weight bearing on misaligned joints often results in osteoarthritis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Che et al. 2016). While treatment with oral phosphate and active vitamin D compounds, such as 1,25(OH)2D3, are a common therapy for XLH, treatment from infancy results in the best outcomes for children suffering with XLH ADDIN EN.CITE <EndNote><Cite><Author>Makitie</Author><Year>2003</Year><RecNum>22</RecNum><DisplayText>(Makitie et al. 2003)</DisplayText><record><rec-number>22</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519794285″>22</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Makitie, O.</author><author>Doria, A.</author><author>Kooh, S. W.</author><author>Cole, W. G.</author><author>Daneman, A.</author><author>Sochett, E.</author></authors></contributors><auth-address>Division of Endocrinology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8. [email protected]</auth-address><titles><title>Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets</title><secondary-title>J Clin Endocrinol Metab</secondary-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><pages>3591-7</pages><volume>88</volume><number>8</number><keywords><keyword>Age of Onset</keyword><keyword>Body Height/drug effects</keyword><keyword>Bone and Bones/diagnostic imaging</keyword><keyword>Calcitriol/blood</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Growth/*drug effects</keyword><keyword>Humans</keyword><keyword>Hypophosphatemia/blood</keyword><keyword>Hypophosphatemia, Familial/diagnostic imaging/metabolism/*therapy</keyword><keyword>Infant</keyword><keyword>Radiography</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2003</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0021-972X (Print) 0021-972X (Linking)</isbn><accession-num>12915641</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/12915641</url></related-urls></urls><electronic-resource-num>10.1210/jc.2003-030036</electronic-resource-num></record></Cite></EndNote>(Makitie et al. 2003). However, treatment of XLH patients frequently results either in severe side effects such as hypercalcaemia, or has no positive effects on bone health ADDIN EN.CITE <EndNote><Cite><Author>Makitie</Author><Year>2003</Year><RecNum>22</RecNum><DisplayText>(Makitie et al. 2003)</DisplayText><record><rec-number>22</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519794285″>22</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Makitie, O.</author><author>Doria, A.</author><author>Kooh, S. W.</author><author>Cole, W. G.</author><author>Daneman, A.</author><author>Sochett, E.</author></authors></contributors><auth-address>Division of Endocrinology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8. [email protected]</auth-address><titles><title>Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets</title><secondary-title>J Clin Endocrinol Metab</secondary-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><pages>3591-7</pages><volume>88</volume><number>8</number><keywords><keyword>Age of Onset</keyword><keyword>Body Height/drug effects</keyword><keyword>Bone and Bones/diagnostic imaging</keyword><keyword>Calcitriol/blood</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Growth/*drug effects</keyword><keyword>Humans</keyword><keyword>Hypophosphatemia/blood</keyword><keyword>Hypophosphatemia, Familial/diagnostic imaging/metabolism/*therapy</keyword><keyword>Infant</keyword><keyword>Radiography</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2003</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0021-972X (Print) 0021-972X (Linking)</isbn><accession-num>12915641</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/12915641</url></related-urls></urls><electronic-resource-num>10.1210/jc.2003-030036</electronic-resource-num></record></Cite></EndNote>(Makitie et al. 2003). While recent developments have provided new therapeutic options, numerous side effects have been reported ADDIN EN.CITE <EndNote><Cite><Author>Carpenter</Author><Year>2011</Year><RecNum>98</RecNum><DisplayText>(Carpenter et al. 2011)</DisplayText><record><rec-number>98</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1536560091″>98</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Carpenter, T. O.</author><author>Imel, E. A.</author><author>Holm, I. A.</author><author>Jan de Beur, S. M.</author><author>Insogna, K. L.</author></authors></contributors><auth-address>Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520-8064, USA. [email protected]</auth-address><titles><title>A clinician&apos;s guide to X-linked hypophosphatemia</title><secondary-title>J Bone Miner Res</secondary-title></titles><periodical><full-title>J Bone Miner Res</full-title></periodical><pages>1381-8</pages><volume>26</volume><number>7</number><edition>2011/05/04</edition><keywords><keyword>*Familial Hypophosphatemic Rickets/diagnostic</keyword><keyword>imaging/pathology/physiopathology/therapy</keyword><keyword>*Genetic Diseases, X-Linked</keyword><keyword>Humans</keyword><keyword>Practice Guidelines as Topic</keyword><keyword>Radiography</keyword></keywords><dates><year>2011</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1523-4681 (Electronic) 0884-0431 (Linking)</isbn><accession-num>21538511</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/21538511</url></related-urls></urls><custom2>PMC3157040</custom2><electronic-resource-num>10.1002/jbmr.340</electronic-resource-num></record></Cite></EndNote>(Carpenter et al. 2011). Thus, further efforts are required to establish effective therapies which heal the under-mineralised bone disorder without causing significant side effects.
23787102134235Figure 2: XLH Pathophysiology ADDIN EN.CITE <EndNote><Cite><Author>Pharmaceutical</Author><Year>2018</Year><RecNum>102</RecNum><DisplayText>(Pharmaceutical 2018)</DisplayText><record><rec-number>102</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1537171348″>102</key></foreign-keys><ref-type name=”Web Page”>12</ref-type><contributors><authors><author>Ultragenyx Pharmaceutical</author></authors></contributors><titles><title>Burosumab for XLH</title></titles><dates><year>2018</year></dates><urls><related-urls><url><style face=”underline” font=”default” size=”100%”>https://www.ultragenyx.com/pipeline/krn23-xlh/</style></url></related-urls></urls></record></Cite></EndNote>(Pharmaceutical 2018)
00Figure 2: XLH Pathophysiology ADDIN EN.CITE <EndNote><Cite><Author>Pharmaceutical</Author><Year>2018</Year><RecNum>102</RecNum><DisplayText>(Pharmaceutical 2018)</DisplayText><record><rec-number>102</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1537171348″>102</key></foreign-keys><ref-type name=”Web Page”>12</ref-type><contributors><authors><author>Ultragenyx Pharmaceutical</author></authors></contributors><titles><title>Burosumab for XLH</title></titles><dates><year>2018</year></dates><urls><related-urls><url><style face=”underline” font=”default” size=”100%”>https://www.ultragenyx.com/pipeline/krn23-xlh/</style></url></related-urls></urls></record></Cite></EndNote>(Pharmaceutical 2018)
The cause of XLH: In XLH, a loss-of-function mutation in the phosphate-regulating endopeptidase homolog, X-linked (PHEX) gene results in excessive levels of the Fibroblast Growth Factor 23 (FGF23) protein PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWlmaGVpdC1OZXN0bGVyPC9BdXRob3I+PFllYXI+MjAx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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWlmaGVpdC1OZXN0bGVyPC9BdXRob3I+PFllYXI+MjAx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ADDIN EN.CITE.DATA (Leifheit-Nestler et al. 2017). Fibroblast Growth Factor 23 (FGF23) is a bone derived hormone that was relatively recently discovered in 2000. FGF23 is mainly produced in two bone cell types, osteoblasts and osteocytes, and is normally produced in response to high levels of circulating phosphorus and active vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D) ADDIN EN.CITE <EndNote><Cite><Author>Erben</Author><Year>2017</Year><RecNum>8</RecNum><DisplayText>(Erben 2017)</DisplayText><record><rec-number>8</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519791986″>8</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Erben, R. G.</author></authors></contributors><auth-address>1 Department of Biomedical Sciences, Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, Vienna, Austria.</auth-address><titles><title>Pleiotropic Actions of FGF23</title><secondary-title>Toxicol Pathol</secondary-title></titles><periodical><full-title>Toxicol Pathol</full-title></periodical><pages>904-910</pages><volume>45</volume><number>7</number><keywords><keyword>bone</keyword><keyword>bone mineralization</keyword><keyword>cardiovascular system</keyword><keyword>endocrine system</keyword><keyword>mineral metabolism</keyword><keyword>renal</keyword><keyword>transgenic animals</keyword></keywords><dates><year>2017</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1533-1601 (Electronic) 0192-6233 (Linking)</isbn><accession-num>29096595</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/29096595</url></related-urls></urls><electronic-resource-num>10.1177/0192623317737469</electronic-resource-num></record></Cite></EndNote>(Erben 2017). In a feedback mechanism, FGF23 is responsible for promoting the excretion of phosphorus as well as reducing 1,25(OH)2D levels (Figure 2) ADDIN EN.CITE <EndNote><Cite><Author>Portale</Author><Year>2012</Year><RecNum>66</RecNum><DisplayText>(Portale, Perwad &amp; Miller 2012)</DisplayText><record><rec-number>66</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533032235″>66</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Book Section”>5</ref-type><contributors><authors><author>Portale, Anthony A.</author><author>Perwad, Farzana</author><author>Miller, Walter L.</author></authors></contributors><titles><title>Rickets Due to Hereditary Abnormalities of Vitamin D Synthesis or Action</title><secondary-title>Pediatric Bone</secondary-title></titles><pages>679-698</pages><dates><year>2012</year></dates><isbn>9780123820402</isbn><urls></urls><electronic-resource-num>10.1016/b978-0-12-382040-2.10025-5</electronic-resource-num></record></Cite></EndNote>(Portale, Perwad & Miller 2012). In XLH, elevated FGF23 levels prevent the renal proximal tubular phosphate reabsorption, by reducing Sodium-Phosphate transporters (NaPi2a and NaPi2c) as well as inhibits the intestinal sodium-phosphate transporter (NaPi2b), resulting in inappropriately high phosphate wasting PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj
TnVtPjU4PC9SZWNOdW0+PERpc3BsYXlUZXh0PihLaWRvIGV0IGFsLiAyMDEzKTwvRGlzcGxheVRl
eHQ+PHJlY29yZD48cmVjLW51bWJlcj41ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg
YXBwPSJFTiIgZGItaWQ9Inhmd2Z4czl2MnpycGU5ZXIyYTlwd2Q5Znh2NXoydjkyd2U1ZCIgdGlt
ZXN0YW1wPSIxNTMzMDMyMTAzIj41ODwva2V5PjxrZXkgYXBwPSJFTldlYiIgZGItaWQ9IiI+MDwv
a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y
ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+S2lkbywgUy48L2F1dGhvcj48
YXV0aG9yPkthbmVrbywgSS48L2F1dGhvcj48YXV0aG9yPlRhdHN1bWksIFMuPC9hdXRob3I+PGF1
dGhvcj5TZWdhd2EsIEguPC9hdXRob3I+PGF1dGhvcj5NaXlhbW90bywgSy48L2F1dGhvcj48L2F1
dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE1vbGVjdWxh
ciBOdXRyaXRpb24sIFVuaXZlcnNpdHkgb2YgVG9rdXNoaW1hIEdyYWR1YXRlIFNjaG9vbCwgMy0x
OC0xNSBLdXJhbW90by1jaG8sIFRva3VzaGltYSwgSmFwYW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxl
cz48dGl0bGU+Vml0YW1pbiBEIGFuZCB0eXBlIElJIHNvZGl1bS1kZXBlbmRlbnQgcGhvc3BoYXRl
IGNvdHJhbnNwb3J0ZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNvbnRyaWIgTmVwaHJvbDwv
c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkNvbnRyaWIg
TmVwaHJvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjg2LTk3PC9wYWdlcz48dm9s
dW1lPjE4MDwvdm9sdW1lPjxlZGl0aW9uPjIwMTMvMDUvMDk8L2VkaXRpb24+PGtleXdvcmRzPjxr
ZXl3b3JkPkFic29ycHRpb248L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5
d29yZD5DYWxjaXRyaW9sL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2FsY2l1bSwgRGll
dGFyeS90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBLaWRuZXkgRGlz
ZWFzZS1NaW5lcmFsIGFuZCBCb25lIERpc29yZGVyL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv
cmQ+RmFtaWxpYWwgSHlwb3Bob3NwaGF0ZW1pYyBSaWNrZXRzL2RpZXQgdGhlcmFweS9tZXRhYm9s
aXNtPC9rZXl3b3JkPjxrZXl3b3JkPkZpYnJvYmxhc3QgR3Jvd3RoIEZhY3RvcnMvcGh5c2lvbG9n
eTwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Npb24gUmVndWxhdGlvbjwva2V5d29yZD48
a2V5d29yZD5HbHVjdXJvbmlkYXNlL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5z
PC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9waG9zcGhhdGVtaWEvcGh5c2lvcGF0aG9sb2d5PC9rZXl3
b3JkPjxrZXl3b3JkPkludGVzdGluYWwgQWJzb3JwdGlvbjwva2V5d29yZD48a2V5d29yZD5LaWRu
ZXkgVHVidWxlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtl
eXdvcmQ+TWljZSwgS25vY2tvdXQ8L2tleXdvcmQ+PGtleXdvcmQ+UGFyYXRoeXJvaWQgSG9ybW9u
ZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaGF0ZXMvKm1ldGFib2xpc208L2tl
eXdvcmQ+PGtleXdvcmQ+UGhvc3Bob3J1cywgRGlldGFyeS9waGFybWFjb2tpbmV0aWNzPC9rZXl3
b3JkPjxrZXl3b3JkPlJlY2VwdG9ycywgQ2FsY2l0cmlvbC9kZWZpY2llbmN5L3BoeXNpb2xvZ3k8
L2tleXdvcmQ+PGtleXdvcmQ+U29kaXVtLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlNv
ZGl1bS1QaG9zcGhhdGUgQ290cmFuc3BvcnRlciBQcm90ZWlucywgVHlwZSBJSS8qbWV0YWJvbGlz
bTwva2V5d29yZD48a2V5d29yZD5WaXRhbWluIEQvKm1ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3
b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48L2RhdGVzPjxpc2JuPjE2NjItMjc4MiAoRWxl
Y3Ryb25pYykmI3hEOzAzMDItNTE0NCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjM2
NTI1NTI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3
Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzNjUyNTUyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91
cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTU5LzAwMDM0Njc4NjwvZWxlY3Ryb25p
Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE.DATA (Kido et al. 2013). Excess FGF23 levels also acts to markedly reduce 1,25(OH)2D levels both by supressing the 25-hydroxyvitamin D 1?-hydroxylase enzyme, CYP27B1, which is responsible for the conversion of inactive vitamin D (25(OH)D) to 1,25(OH)2D, and by inducing the 25-hydroxyvitamin D 24-hydroxylase enzyme, CYP24A1, which acts to convert 1,25(OH)2D, as well as 25(OH)D, to inactive metabolites PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Liu et al. 2016).

The role of phosphate in XLH: Phosphate, whilst less tightly regulated than calcium, plays a critical role in bone homeostasis including directly contributing to chondrocyte maturation and skeletal mineralisation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LbzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LbzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051
bT41PC9SZWNOdW0+PERpc3BsYXlUZXh0PihLbyBldCBhbC4gMjAxNik8L0Rpc3BsYXlUZXh0Pjxy
ZWNvcmQ+PHJlYy1udW1iZXI+NTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF
TiIgZGItaWQ9Inhmd2Z4czl2MnpycGU5ZXIyYTlwd2Q5Znh2NXoydjkyd2U1ZCIgdGltZXN0YW1w
PSIxNTE5NzkxNjc3Ij41PC9rZXk+PGtleSBhcHA9IkVOV2ViIiBkYi1pZD0iIj4wPC9rZXk+PC9m
b3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBl
Pjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LbywgRi4gQy48L2F1dGhvcj48YXV0aG9y
Pk1hcnRpbnMsIEouIFMuPC9hdXRob3I+PGF1dGhvcj5SZWRkeSwgUC48L2F1dGhvcj48YXV0aG9y
PkJyYWdkb24sIEIuPC9hdXRob3I+PGF1dGhvcj5IdXNzZWluLCBBLiBJLjwvYXV0aG9yPjxhdXRo
b3I+R2Vyc3RlbmZlbGQsIEwuIEMuPC9hdXRob3I+PGF1dGhvcj5EZW1heSwgTS4gQi48L2F1dGhv
cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5FbmRvY3JpbmUgVW5pdCwg
TWFzc2FjaHVzZXR0cyBHZW5lcmFsIEhvc3BpdGFsLCBCb3N0b24sIE1BLCBVU0EuJiN4RDtIYXJ2
YXJkIE1lZGljYWwgU2Nob29sLCBCb3N0b24sIE1BLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIE9y
dGhvcGFlZGljIFN1cmdlcnksIEJvc3RvbiBVbml2ZXJzaXR5IFNjaG9vbCBvZiBNZWRpY2luZSwg
Qm9zdG9uLCBNQSwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkFjdXRlIFBob3Nw
aGF0ZSBSZXN0cmljdGlvbiBJbXBhaXJzIEJvbmUgRm9ybWF0aW9uIGFuZCBJbmNyZWFzZXMgTWFy
cm93IEFkaXBvc2UgVGlzc3VlIGluIEdyb3dpbmcgTWljZTwvdGl0bGU+PHNlY29uZGFyeS10aXRs
ZT5KIEJvbmUgTWluZXIgUmVzPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+
PGZ1bGwtdGl0bGU+SiBCb25lIE1pbmVyIFJlczwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBh
Z2VzPjIyMDQtMjIxNDwvcGFnZXM+PHZvbHVtZT4zMTwvdm9sdW1lPjxudW1iZXI+MTI8L251bWJl
cj48a2V5d29yZHM+PGtleXdvcmQ+QWRpcG9jeXRlcy9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdv
cmQ+QWRpcG9zZSBUaXNzdWUvKnBhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9r
ZXl3b3JkPjxrZXl3b3JkPkJvZHkgQ29tcG9zaXRpb248L2tleXdvcmQ+PGtleXdvcmQ+Qm9uZSBN
YXJyb3cvYmxvb2Qgc3VwcGx5LypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Qm9uZSBNb3Jw
aG9nZW5ldGljIFByb3RlaW5zL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+Qm9uZSBSZXNv
cnB0aW9uL3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5DZWxsIERpZmZlcmVudGlhdGlvbjwv
a2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48
a2V5d29yZD5NZXNlbmNoeW1hbCBTdHJvbWFsIENlbGxzL21ldGFib2xpc208L2tleXdvcmQ+PGtl
eXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5Pc3Rlb2JsYXN0cy9tZXRhYm9saXNtL3BhdGhv
bG9neTwva2V5d29yZD48a2V5d29yZD4qT3N0ZW9nZW5lc2lzPC9rZXl3b3JkPjxrZXl3b3JkPlBo
b3NwaGF0ZXMvKmRlZmljaWVuY3k8L2tleXdvcmQ+PGtleXdvcmQ+U2lnbmFsIFRyYW5zZHVjdGlv
bjwva2V5d29yZD48a2V5d29yZD5Cb25lIGhpc3RvbW9ycGhvbWV0cnk8L2tleXdvcmQ+PGtleXdv
cmQ+Qm9uZS1mYXQgaW50ZXJhY3Rpb25zPC9rZXl3b3JkPjxrZXl3b3JkPkRpc29yZGVycyBvZiBj
YWxjaXVtIGFuZCBwaG9zcGhhdGUgbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl
cz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RGVjPC9kYXRlPjwvcHViLWRhdGVz
PjwvZGF0ZXM+PGlzYm4+MTUyMy00NjgxIChFbGVjdHJvbmljKSYjeEQ7MDg4NC0wNDMxIChMaW5r
aW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNzMyNDE3NzwvYWNjZXNzaW9uLW51bT48dXJscz48
cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjcz
MjQxNzc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVt
PjEwLjEwMDIvamJtci4yODkxPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0Np
dGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE.DATA (Ko et al. 2016). The main regulator of serum phosphate levels is FGF23. However, Parathyroid Hormone (PTH), and 1,25(OH)2D contribute to the regulation of phosphate levels as well ADDIN EN.CITE <EndNote><Cite><Author>Razzaque</Author><Year>2007</Year><RecNum>62</RecNum><DisplayText>(Razzaque &amp; Lanske 2007)</DisplayText><record><rec-number>62</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533032213″>62</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Razzaque, M. S.</author><author>Lanske, B.</author></authors></contributors><auth-address>Department of Developmental Biology, Harvard School of Dental Medicine, Research and Education Building, Room # 304, 190 Longwood Avenue, Boston, Massachusetts 02115, USA. [email protected]</auth-address><titles><title>The emerging role of the fibroblast growth factor-23-klotho axis in renal regulation of phosphate homeostasis</title><secondary-title>J Endocrinol</secondary-title></titles><periodical><full-title>J Endocrinol</full-title></periodical><pages>1-10</pages><volume>194</volume><number>1</number><edition>2007/06/27</edition><keywords><keyword>Animals</keyword><keyword>Bone and Bones/metabolism</keyword><keyword>Fibroblast Growth Factors/genetics/*physiology</keyword><keyword>Glucuronidase/genetics/*physiology</keyword><keyword>Homeostasis</keyword><keyword>Humans</keyword><keyword>Iron/metabolism</keyword><keyword>Kidney/*metabolism</keyword><keyword>Mice</keyword><keyword>Mice, Transgenic</keyword><keyword>Models, Animal</keyword><keyword>Phosphates/metabolism</keyword><keyword>Signal Transduction/*physiology</keyword></keywords><dates><year>2007</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0022-0795 (Print) 0022-0795 (Linking)</isbn><accession-num>17592015</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/17592015</url></related-urls></urls><custom2>PMC2900827</custom2><electronic-resource-num>10.1677/JOE-07-0095</electronic-resource-num></record></Cite></EndNote>(Razzaque & Lanske 2007). As discussed, in XLH, elevated FGF23 levels prevent the renal proximal tubular phosphate reabsorption, by reducing Sodium-Phosphate transporters (NaPi2a and NaPi2c) as well as inhibits the intestinal sodium-phosphate transporter (NaPi2b) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3dlPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3dlPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (Bowe et al. 2001). When supplemented with phosphate alone, XLH patients show a partial improvement in the rachitic phenotype, but no improvement in endosteal bone mineralisation ADDIN EN.CITE <EndNote><Cite><Author>Marie</Author><Year>1981</Year><RecNum>17</RecNum><DisplayText>(Marie, Travers &amp; Glorieux 1981)</DisplayText><record><rec-number>17</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519793688″>17</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P. J.</author><author>Travers, R.</author><author>Glorieux, F. H.</author></authors></contributors><titles><title>Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse</title><secondary-title>Journal of Clinical Investigation</secondary-title></titles><periodical><full-title>Journal of Clinical Investigation</full-title></periodical><pages>911-914</pages><volume>67</volume><number>3</number><dates><year>1981</year></dates><isbn>0021-9738</isbn><urls></urls><electronic-resource-num>10.1172/jci110110</electronic-resource-num></record></Cite></EndNote>(Marie, Travers & Glorieux 1981). This effect of phosphate is considered to directly effect chondrocyte differentiation and apoptosis. Phosphate activates the caspase-9-dependant mitochondrial pathway to mediate hypertrophic chondrocyte apoptosis. This activation is critical for growth plate maturation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWJiYWdoPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWJiYWdoPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48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ADDIN EN.CITE.DATA (Sabbagh, Carpenter & Demay 2005). The growth plate is responsible for the longitudinal endochondral ossification and determines the final length of the bone PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GdWVudGU8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GdWVudGU8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS
ZWNOdW0+MzA8L1JlY051bT48RGlzcGxheVRleHQ+KEZ1ZW50ZSBldCBhbC4gMjAxNyk8L0Rpc3Bs
YXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48
a2V5IGFwcD0iRU4iIGRiLWlkPSJ4ZndmeHM5djJ6cnBlOWVyMmE5cHdkOWZ4djV6MnY5MndlNWQi
IHRpbWVzdGFtcD0iMTUyMDIwNzUzNyI+MzA8L2tleT48a2V5IGFwcD0iRU5XZWIiIGRiLWlkPSIi
PjA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x
NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkZ1ZW50ZSwgUi48L2F1
dGhvcj48YXV0aG9yPkdpbC1QZW5hLCBILjwvYXV0aG9yPjxhdXRob3I+Q2xhcmFtdW50LVRhYmVy
bmVyLCBELjwvYXV0aG9yPjxhdXRob3I+SGVybmFuZGV6LCBPLjwvYXV0aG9yPjxhdXRob3I+RmVy
bmFuZGV6LUlnbGVzaWFzLCBBLjwvYXV0aG9yPjxhdXRob3I+QWxvbnNvLUR1cmFuLCBMLjwvYXV0
aG9yPjxhdXRob3I+Um9kcmlndWV6LVJ1YmlvLCBFLjwvYXV0aG9yPjxhdXRob3I+U2FudG9zLCBG
LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9u
IG9mIFBlZGlhdHJpY3MsIERlcGFydG1lbnQgb2YgTWVkaWNpbmUuIEZhY3VsdHkgb2YgTWVkaWNp
bmUsIFVuaXZlcnNpdHkgb2YgT3ZpZWRvLCBPdmllZG8sIEFzdHVyaWFzLCBTcGFpbi4mI3hEO0Rl
cGFydG1lbnQgb2YgUGVkaWF0cmljcywgSG9zcGl0YWwgVW5pdmVyc2l0YXJpbyBDZW50cmFsIGRl
IEFzdHVyaWFzIChIVUNBKSwgT3ZpZWRvLCBBc3R1cmlhcywgU3BhaW4uJiN4RDtEaXZpc2lvbiBv
ZiBQZWRpYXRyaWNzLCBEZXBhcnRtZW50IG9mIE1lZGljaW5lLiBGYWN1bHR5IG9mIE1lZGljaW5l
LCBVbml2ZXJzaXR5IG9mIE92aWVkbywgT3ZpZWRvLCBBc3R1cmlhcywgU3BhaW4uIGZzYW50b3NA
dW5pb3ZpLmVzLiYjeEQ7RGVwYXJ0bWVudCBvZiBQZWRpYXRyaWNzLCBIb3NwaXRhbCBVbml2ZXJz
aXRhcmlvIENlbnRyYWwgZGUgQXN0dXJpYXMgKEhVQ0EpLCBPdmllZG8sIEFzdHVyaWFzLCBTcGFp
bi4gZnNhbnRvc0B1bmlvdmkuZXMuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+WC1saW5r
ZWQgaHlwb3Bob3NwaGF0ZW1pYSBhbmQgZ3Jvd3RoPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlJl
diBFbmRvY3IgTWV0YWIgRGlzb3JkPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj
YWw+PGZ1bGwtdGl0bGU+UmV2IEVuZG9jciBNZXRhYiBEaXNvcmQ8L2Z1bGwtdGl0bGU+PC9wZXJp
b2RpY2FsPjxwYWdlcz4xMDctMTE1PC9wYWdlcz48dm9sdW1lPjE4PC92b2x1bWU+PG51bWJlcj4x
PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+RmFt
aWxpYWwgSHlwb3Bob3NwaGF0ZW1pYyBSaWNrZXRzL2NvbXBsaWNhdGlvbnMvKm1ldGFib2xpc208
L2tleXdvcmQ+PGtleXdvcmQ+Rmlicm9ibGFzdCBHcm93dGggRmFjdG9ycy8qbWV0YWJvbGlzbTwv
a2V5d29yZD48a2V5d29yZD5Hcm93dGggRGlzb3JkZXJzL2RydWcgdGhlcmFweS9ldGlvbG9neS8q
bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+KkJv
bmU8L2tleXdvcmQ+PGtleXdvcmQ+Kkdyb3d0aDwva2V5d29yZD48a2V5d29yZD4qR3Jvd3RoIHBs
YXRlPC9rZXl3b3JkPjxrZXl3b3JkPipIeXBvcGhvc3BoYXRlbWlhPC9rZXl3b3JkPjxrZXl3b3Jk
PipQaG9zcGhhdGU8L2tleXdvcmQ+PGtleXdvcmQ+KlJpY2tldHM8L2tleXdvcmQ+PC9rZXl3b3Jk
cz48ZGF0ZXM+PHllYXI+MjAxNzwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1hcjwvZGF0ZT48L3B1
Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NzMtMjYwNiAoRWxlY3Ryb25pYykmI3hEOzEzODktOTE1
NSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjgxMzA2MzQ8L2FjY2Vzc2lvbi1udW0+
PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVi
bWVkLzI4MTMwNjM0PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291
cmNlLW51bT4xMC4xMDA3L3MxMTE1NC0wMTctOTQwOC0xPC9lbGVjdHJvbmljLXJlc291cmNlLW51
bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE.DATA (Fuente et al. 2017). In the mouse model of XLH (HYP mice) abnormalities of the growth plate are put down to the role of FGF23 in inhibiting chondrocyte proliferation and differentiation. The marked deformities and alterations in the chondrocyte-ossification margin and primary spongiosa trabeculae in HYP mice strongly mimic the deformed growth plate seen in XLH patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GdWVudGU8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GdWVudGU8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS
ZWNOdW0+MTA3PC9SZWNOdW0+PERpc3BsYXlUZXh0PihGdWVudGUgZXQgYWwuIDIwMTgpPC9EaXNw
bGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEwNzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz
PjxrZXkgYXBwPSJFTiIgZGItaWQ9Inhmd2Z4czl2MnpycGU5ZXIyYTlwd2Q5Znh2NXoydjkyd2U1
ZCIgdGltZXN0YW1wPSIxNTM3MTczOTI1Ij4xMDc8L2tleT48a2V5IGFwcD0iRU5XZWIiIGRiLWlk
PSIiPjA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xl
Ij4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkZ1ZW50ZSwgUi48
L2F1dGhvcj48YXV0aG9yPkdpbC1QZW5hLCBILjwvYXV0aG9yPjxhdXRob3I+Q2xhcmFtdW50LVRh
YmVybmVyLCBELjwvYXV0aG9yPjxhdXRob3I+SGVybmFuZGV6LUZyaWFzLCBPLjwvYXV0aG9yPjxh
dXRob3I+RmVybmFuZGV6LUlnbGVzaWFzLCBBLjwvYXV0aG9yPjxhdXRob3I+SGVybWlkYS1QcmFk
bywgRi48L2F1dGhvcj48YXV0aG9yPkFuZXMtR29uemFsZXosIEcuPC9hdXRob3I+PGF1dGhvcj5S
dWJpby1BbGlhZ2EsIEkuPC9hdXRob3I+PGF1dGhvcj5Mb3BleiwgSi4gTS48L2F1dGhvcj48YXV0
aG9yPlNhbnRvcywgRi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk
cmVzcz5EaXZpc2lvbiBvZiBQZWRpYXRyaWNzLCBEZXBhcnRtZW50IG9mIE1lZGljaW5lLCBGYWN1
bHR5IG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIE92aWVkbywgT3ZpZWRvLCBBc3R1cmlhcywg
U3BhaW47IEhhcnZhcmQgU2Nob29sIG9mIERlbnRhbCBNZWRpY2luZSwgRGV2ZWxvcG1lbnRhbCBC
aW9sb2d5LCBIYXJ2YXJkIFVuaXZlcnNpdHksIEJvc3RvbiwgTUEsIFVTQS4mI3hEO0RlcGFydG1l
bnQgb2YgUGVkaWF0cmljcywgSG9zcGl0YWwgVW5pdmVyc2l0YXJpbyBDZW50cmFsIGRlIEFzdHVy
aWFzIChIVUNBKSwgT3ZpZWRvLCBBc3R1cmlhcywgU3BhaW4uIEVsZWN0cm9uaWMgYWRkcmVzczog
aGdpbHBlbmFAZ21haWwuY29tLiYjeEQ7RGl2aXNpb24gb2YgUGVkaWF0cmljcywgRGVwYXJ0bWVu
dCBvZiBNZWRpY2luZSwgRmFjdWx0eSBvZiBNZWRpY2luZSwgVW5pdmVyc2l0eSBvZiBPdmllZG8s
IE92aWVkbywgQXN0dXJpYXMsIFNwYWluLiYjeEQ7RGVwYXJ0bWVudCBvZiBPdG9sYXJ5bmdvbG9n
aXN0LCBIb3NwaXRhbCBVbml2ZXJzaXRhcmlvIENlbnRyYWwgZGUgQXN0dXJpYXMsIEluc3RpdHV0
byBVbml2ZXJzaXRhcmlvIGRlIE9uY29sb2dpYSBkZWwgUHJpbmNpcGFkbyBkZSBBc3R1cmlhcywg
T3ZpZWRvLCBTcGFpbi4mI3hEO0RlcGFydG1lbnQgb2YgUGVkaWF0cmljcywgSG9zcGl0YWwgVW5p
dmVyc2l0YXJpbyBDZW50cmFsIGRlIEFzdHVyaWFzIChIVUNBKSwgT3ZpZWRvLCBBc3R1cmlhcywg
U3BhaW4uJiN4RDtVbml2ZXJzaXR5IG9mIFp1cmljaCwgSW5zdGl0dXRlIG9mIFBoeXNpb2xvZ3ks
IEtpZG5leSBhbmQgQWNpZC1iYXNlIFBoeXNpb2xvZ3kgR3JvdXAsIFp1cmljaCwgU3dpdHplcmxh
bmQuJiN4RDtEaXZpc2lvbiBvZiBQZWRpYXRyaWNzLCBEZXBhcnRtZW50IG9mIE1lZGljaW5lLCBG
YWN1bHR5IG9mIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIE92aWVkbywgT3ZpZWRvLCBBc3R1cmlh
cywgU3BhaW47IERlcGFydG1lbnQgb2YgUGVkaWF0cmljcywgSG9zcGl0YWwgVW5pdmVyc2l0YXJp
byBDZW50cmFsIGRlIEFzdHVyaWFzIChIVUNBKSwgT3ZpZWRvLCBBc3R1cmlhcywgU3BhaW4uPC9h
dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+TWFya2VkIGFsdGVyYXRpb25zIGluIHRoZSBzdHJ1
Y3R1cmUsIGR5bmFtaWNzIGFuZCBtYXR1cmF0aW9uIG9mIGdyb3d0aCBwbGF0ZSBsaWtlbHkgZXhw
bGFpbiBncm93dGggcmV0YXJkYXRpb24gYW5kIGJvbmUgZGVmb3JtaXRpZXMgb2YgeW91bmcgSHlw
IG1pY2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Qm9uZTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0
bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkJvbmU8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs
PjxwYWdlcz4xODctMTk1PC9wYWdlcz48dm9sdW1lPjExNjwvdm9sdW1lPjxlZGl0aW9uPjIwMTgv
MDgvMTE8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkJvbmU8L2tleXdvcmQ+PGtleXdvcmQ+
Q2hvbmRyb2N5dGVzPC9rZXl3b3JkPjxrZXl3b3JkPkdyb3d0aCBwbGF0ZTwva2V5d29yZD48a2V5
d29yZD5SaWNrZXRzPC9rZXl3b3JkPjxrZXl3b3JkPlhsaDwva2V5d29yZD48L2tleXdvcmRzPjxk
YXRlcz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXVnIDg8L2RhdGU+PC9wdWIt
ZGF0ZXM+PC9kYXRlcz48aXNibj4xODczLTI3NjMgKEVsZWN0cm9uaWMpJiN4RDsxODczLTI3NjMg
KExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjMwMDk2NDY4PC9hY2Nlc3Npb24tbnVtPjx1
cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1l
ZC8zMDA5NjQ2ODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJj
ZS1udW0+MTAuMTAxNi9qLmJvbmUuMjAxOC4wOC4wMDQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVt
PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+
ADDIN EN.CITE.DATA (Fuente et al. 2018).
Consistent with the effect of phosphate on the growth plate, phosphate supplementation only works in the children where the activity of growth plate is significant. No benefits of phosphate were observed in adult patients with osteomalacia ADDIN EN.CITE <EndNote><Cite><Author>Marie</Author><Year>1981</Year><RecNum>17</RecNum><DisplayText>(Marie, Travers &amp; Glorieux 1981)</DisplayText><record><rec-number>17</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519793688″>17</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P. J.</author><author>Travers, R.</author><author>Glorieux, F. H.</author></authors></contributors><titles><title>Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse</title><secondary-title>Journal of Clinical Investigation</secondary-title></titles><periodical><full-title>Journal of Clinical Investigation</full-title></periodical><pages>911-914</pages><volume>67</volume><number>3</number><dates><year>1981</year></dates><isbn>0021-9738</isbn><urls></urls><electronic-resource-num>10.1172/jci110110</electronic-resource-num></record></Cite></EndNote>(Marie, Travers & Glorieux 1981).
Phosphate plays a critical role in the mineralisation of the skeleton. The formation of hydroxyapatite (HAP) in the skeleton requires a combination of inorganic Phosphate (Pi) with calcium (Ca) (Figure 3) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb3N0ZXI8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb3N0ZXI8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Foster et al. 2012). The presentation of inorganic phosphate for combination with calcium is not dependent on serum phosphate levels, but rather by the co-ordinated production by osteoblasts PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb3N0ZXI8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb3N0ZXI8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Foster et al. 2012). This process is governed by at least three cell membrane associated proteins Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (NPP1), 3376295435610Figure 3: The mechanism of coordinated bone mineralisation in osteocytes.

Figure 3: The mechanism of coordinated bone mineralisation in osteocytes.

Progressive Ankylosis Protein (ANK) and Tissue Non-specific Alkaline Phosphatase (TNAP) ADDIN EN.CITE <EndNote><Cite><Author>Harmey</Author><Year>2004</Year><RecNum>104</RecNum><DisplayText>(Harmey et al. 2004)</DisplayText><record><rec-number>104</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1537172106″>104</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Harmey, Dympna</author><author>Hessle, Lovisa</author><author>Narisawa, Sonoko</author><author>Johnson, Kristen A.</author><author>Terkeltaub, Robert</author><author>Millán, José Luis</author></authors></contributors><titles><title>Concerted Regulation of Inorganic Pyrophosphate and Osteopontin by Akp2, Enpp1, and Ank</title><secondary-title>The American Journal of Pathology</secondary-title></titles><periodical><full-title>The American Journal of Pathology</full-title></periodical><pages>1199-1209</pages><volume>164</volume><number>4</number><section>1199</section><dates><year>2004</year></dates><isbn>00029440</isbn><urls></urls><electronic-resource-num>10.1016/s0002-9440(10)63208-7</electronic-resource-num></record></Cite></EndNote>(Harmey et al. 2004). Conversion of pyrophosphate (PPi) to Pi by TNAP is common to mineralising osteoblasts. A high PPi to Pi ratio has been shown to be inhibitory for HAP formation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWxsYW48L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWxsYW48L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Millan 2013). In the mouse model of XLH (Hyp mice), excessive FGF23 contributes to PPi accumulation, by reducing TNAP expression and decreasing the conversion to Pi PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdXJhbGk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdXJhbGk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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=
ADDIN EN.CITE.DATA (Murali et al. 2016). These data partly explain why elevating serum phosphate levels does not contribute to improving bone mineralisation in XLH. Furthermore, the key to improving bone mineralisation in XLH may lie in reducing PPi:Pi ratio through regulation of one or more osteoblastic genes in the bone mineralisation pathway. 336359512700Figure 4: Basic principles of vitamin D synthesis and catabolism.

Figure 4: Basic principles of vitamin D synthesis and catabolism.

Vitamin D therapy and XLH: The vitamin D endocrine system is responsible for the maintenance of calcium homoeostasis and skeletal growth ADDIN EN.CITE <EndNote><Cite><Author>Rowling</Author><Year>2007</Year><RecNum>81</RecNum><DisplayText>(Rowling, Matthew J et al. 2007)</DisplayText><record><rec-number>81</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533113728″>81</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Rowling, Matthew J</author><author>Gliniak, Christy</author><author>Welsh, JoEllen</author><author>Fleet, James C</author></authors></contributors><titles><title>High dietary vitamin D prevents hypocalcemia and osteomalacia in CYP27B1 knockout mice</title><secondary-title>The Journal of nutrition</secondary-title></titles><periodical><full-title>The Journal of nutrition</full-title></periodical><pages>2608-2615</pages><volume>137</volume><number>12</number><dates><year>2007</year></dates><isbn>0022-3166</isbn><urls><related-urls><url>https://watermark.silverchair.com/2608.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAcAwggG8BgkqhkiG9w0BBwagggGtMIIBqQIBADCCAaIGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMpmD_KmwRd4sGvFgjAgEQgIIBc6dnUxoCZL1YaBZdkc2ucI5X1-RQfXvPZWKQ02OVcRZZvOFjl1Fz9SCa38bb7d0d5Vcljd1q1Vk8la1MlnM7PMUNOyzIRx45OQEB8TooskRO12tczIL0gsaABrtQppQkj0WZQua03_RzIAmUbsDWE_cdlbotQBj7iAISYqr0c1s7JT8xPz7I3tRf6i2QNLpI106GHBW_VJGveUsgo1UDr3ZvlVx0esTI587hPzZaRYsGaYI6NPZI5RqgjQoCMaIaIOfLdD2wB7r094DMgSOrQLtaGD3HUoBbsaJBgOX_Uq7WA3m4leOAGp2gsvWHh8zXyWH4bzJZP6Rcb_Y1m4T4pRO_jRrFNDOngvpP-REW63Mx55_cj3vzDYXc8J7Erzi-NMh47kE2n53mnes4hDMin3TpPqg0LV9f958aKTvcVHdD1ih-kicgSYa12aDVlKfjb3hpP90p13eZfJh3dvEDS8OmEgBaLHu9TbopBiELK2nrEm-4</url></related-urls></urls></record></Cite></EndNote>(Rowling, Matthew J et al. 2007). Optimal bone health is achieved when adequate vitamin D is metabolised and mediated properly through genes in the intestine, kidney, and bone ADDIN EN.CITE <EndNote><Cite><Author>Rowling</Author><Year>2007</Year><RecNum>81</RecNum><DisplayText>(Rowling, Matthew J et al. 2007)</DisplayText><record><rec-number>81</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533113728″>81</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Rowling, Matthew J</author><author>Gliniak, Christy</author><author>Welsh, JoEllen</author><author>Fleet, James C</author></authors></contributors><titles><title>High dietary vitamin D prevents hypocalcemia and osteomalacia in CYP27B1 knockout mice</title><secondary-title>The Journal of nutrition</secondary-title></titles><periodical><full-title>The Journal of nutrition</full-title></periodical><pages>2608-2615</pages><volume>137</volume><number>12</number><dates><year>2007</year></dates><isbn>0022-3166</isbn><urls><related-urls><url>https://watermark.silverchair.com/2608.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAcAwggG8BgkqhkiG9w0BBwagggGtMIIBqQIBADCCAaIGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMpmD_KmwRd4sGvFgjAgEQgIIBc6dnUxoCZL1YaBZdkc2ucI5X1-RQfXvPZWKQ02OVcRZZvOFjl1Fz9SCa38bb7d0d5Vcljd1q1Vk8la1MlnM7PMUNOyzIRx45OQEB8TooskRO12tczIL0gsaABrtQppQkj0WZQua03_RzIAmUbsDWE_cdlbotQBj7iAISYqr0c1s7JT8xPz7I3tRf6i2QNLpI106GHBW_VJGveUsgo1UDr3ZvlVx0esTI587hPzZaRYsGaYI6NPZI5RqgjQoCMaIaIOfLdD2wB7r094DMgSOrQLtaGD3HUoBbsaJBgOX_Uq7WA3m4leOAGp2gsvWHh8zXyWH4bzJZP6Rcb_Y1m4T4pRO_jRrFNDOngvpP-REW63Mx55_cj3vzDYXc8J7Erzi-NMh47kE2n53mnes4hDMin3TpPqg0LV9f958aKTvcVHdD1ih-kicgSYa12aDVlKfjb3hpP90p13eZfJh3dvEDS8OmEgBaLHu9TbopBiELK2nrEm-4</url></related-urls></urls></record></Cite></EndNote>(Rowling, Matthew J et al. 2007). While vitamin D can be obtained through diet and supplements, the predominant source for vitamin D is via skin exposure to UV radiation from the sun. Vitamin D3, formed in the skin, is metabolised further in the liver to form 25-hydroxyvitamin D (25(OH)D), mediated primarily by the hepatic enzymes CYP2R1 and CYP27A1 (Figure 4) ADDIN EN.CITE <EndNote><Cite><Author>Henry</Author><Year>2011</Year><RecNum>73</RecNum><DisplayText>(Henry 2011)</DisplayText><record><rec-number>73</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533032276″>73</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Henry, H. L.</author></authors></contributors><auth-address>Department of Biochemistry, University of California, Riverside, CA 92521, USA. [email protected]</auth-address><titles><title>Regulation of vitamin D metabolism</title><secondary-title>Best Pract Res Clin Endocrinol Metab</secondary-title></titles><periodical><full-title>Best Pract Res Clin Endocrinol Metab</full-title></periodical><pages>531-41</pages><volume>25</volume><number>4</number><edition>2011/08/30</edition><keywords><keyword>24,25-Dihydroxyvitamin D 3/metabolism</keyword><keyword>Animals</keyword><keyword>*Autocrine Communication</keyword><keyword>Calcitriol/metabolism</keyword><keyword>Cholestanetriol 26-Monooxygenase/genetics/metabolism</keyword><keyword>*Feedback, Physiological</keyword><keyword>*Gene Expression Regulation, Enzymologic</keyword><keyword>Humans</keyword><keyword>Kidney/metabolism</keyword><keyword>Liver/metabolism</keyword><keyword>*Paracrine Communication</keyword><keyword>*Signal Transduction</keyword><keyword>Steroid Hydroxylases/genetics/metabolism</keyword><keyword>Vitamin D/*metabolism</keyword><keyword>Vitamin D3 24-Hydroxylase</keyword></keywords><dates><year>2011</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1878-1594 (Electronic) 1521-690X (Linking)</isbn><accession-num>21872796</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/21872796</url></related-urls></urls><electronic-resource-num>10.1016/j.beem.2011.05.003</electronic-resource-num></record></Cite></EndNote>(Henry 2011). 25(OH)D is the major circulating metabolite of vitamin D and while it is itself inactive, the circulating levels of 25(OH)D is used clinically to determine a person’s vitamin D status ADDIN EN.CITE ;EndNote;;Cite;;Author;Vieth;/Author;;Year;1999;/Year;;RecNum;38;/RecNum;;DisplayText;(Vieth 1999);/DisplayText;;record;;rec-number;38;/rec-number;;foreign-keys;;key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1522565771″;38;/key;;key app=”ENWeb” db-id=””;0;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Vieth, R.;/author;;/authors;;/contributors;;titles;;title;Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety;/title;;secondary-title;American Journal of Clinical Nutrition ;/secondary-title;;/titles;;periodical;;full-title;American Journal of Clinical Nutrition;/full-title;;/periodical;;pages;842-856;/pages;;volume;69;/volume;;number;5;/number;;dates;;year;1999;/year;;/dates;;urls;;/urls;;/record;;/Cite;;/EndNote;(Vieth 1999). For vitamin D to exert its activity, 25(OH)D is required to be further metabolised to 1,25(OH)2D, a process that is catalysed by the renal CYP27B1 enzyme. 1,25(OH)2D acts upon many tissues by binding to the vitamin D receptor (VDR) and modulating various systems and tissues PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3dsaW5nPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3dsaW5nPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48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ADDIN EN.CITE.DATA (Roizen et al. 2018; Rowling, Matthew J et al. 2007). While the classical action of 1,25(OH)2D is to stimulate intestinal calcium absorption, 1,25(OH)2D has also been shown to regulate several other systems including cardiovascular health, immune system, lung health, anti-neoplastic action in several cancers, skin maturation as well multiple direct roles in bone homeostasis ADDIN EN.CITE ;EndNote;;Cite;;Author;Anderson;/Author;;Year;2017;/Year;;RecNum;94;/RecNum;;DisplayText;(Anderson 2017);/DisplayText;;record;;rec-number;94;/rec-number;;foreign-keys;;key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1534470997″;94;/key;;key app=”ENWeb” db-id=””;0;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Anderson, P. H.;/author;;/authors;;/contributors;;auth-address;Musculoskeletal Biology Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, 5001, Australia. [email protected];/auth-address;;titles;;title;Vitamin D Activity and Metabolism in Bone;/title;;secondary-title;Curr Osteoporos Rep;/secondary-title;;/titles;;periodical;;full-title;Curr Osteoporos Rep;/full-title;;/periodical;;pages;443-449;/pages;;volume;15;/volume;;number;5;/number;;edition;2017/08/16;/edition;;keywords;;keyword;25-Hydroxyvitamin D3 1-alpha-Hydroxylase/*metabolism</keyword><keyword>Autocrine Communication</keyword><keyword>Bone Resorption/metabolism</keyword><keyword>Bone and Bones/*metabolism</keyword><keyword>Calcification, Physiologic/physiology</keyword><keyword>Fracture Healing/physiology</keyword><keyword>Humans</keyword><keyword>Receptors, Calcitriol/*metabolism</keyword><keyword>Vitamin D/*analogs &amp; derivatives/metabolism</keyword><keyword>Vitamin D3 24-Hydroxylase/*metabolism</keyword><keyword>Cyp24a1</keyword><keyword>Cyp27b1</keyword><keyword>Mineralisation</keyword><keyword>Osteoblasts</keyword><keyword>Vitamin D</keyword><keyword>Vitamin D receptor</keyword></keywords><dates><year>2017</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1544-2241 (Electronic) 1544-1873 (Linking)</isbn><accession-num>28808890</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/28808890</url></related-urls></urls><electronic-resource-num>10.1007/s11914-017-0394-8</electronic-resource-num></record></Cite></EndNote>(Anderson 2017).

In XLH, excessive FGF23 actions results in lower renal 1,25(OH)D production. However, few studies have investigated the vitamin D status, as measured by 25(OH)D levels, in XLH patients. This gap in the knowledge is not unexpected given the XLH disease is considered to be disorder that impacts in renal activation of 1,25(OH)D, and not 25(OH)D production. Thus the focus of current therapies include administering 1,25(OH)2D3 to restore levels, or, to use synthetic vitamin D analogues to mimic 1,25(OH)2D3 activity ADDIN EN.CITE <EndNote><Cite><Author>Makitie</Author><Year>2003</Year><RecNum>22</RecNum><DisplayText>(Makitie et al. 2003)</DisplayText><record><rec-number>22</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519794285″>22</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Makitie, O.</author><author>Doria, A.</author><author>Kooh, S. W.</author><author>Cole, W. G.</author><author>Daneman, A.</author><author>Sochett, E.</author></authors></contributors><auth-address>Division of Endocrinology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8. [email protected]</auth-address><titles><title>Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets</title><secondary-title>J Clin Endocrinol Metab</secondary-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><pages>3591-7</pages><volume>88</volume><number>8</number><keywords><keyword>Age of Onset</keyword><keyword>Body Height/drug effects</keyword><keyword>Bone and Bones/diagnostic imaging</keyword><keyword>Calcitriol/blood</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Growth/*drug effects</keyword><keyword>Humans</keyword><keyword>Hypophosphatemia/blood</keyword><keyword>Hypophosphatemia, Familial/diagnostic imaging/metabolism/*therapy</keyword><keyword>Infant</keyword><keyword>Radiography</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2003</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0021-972X (Print) 0021-972X (Linking)</isbn><accession-num>12915641</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/12915641</url></related-urls></urls><electronic-resource-num>10.1210/jc.2003-030036</electronic-resource-num></record></Cite></EndNote>(Makitie et al. 2003). Treatment is often supplied with oral phosphate which can be effective in improving growth, healing, and biochemical parameters in children. However, many children fail to respond to treatment for reasons that are not clear ADDIN EN.CITE <EndNote><Cite><Author>Makitie</Author><Year>2003</Year><RecNum>22</RecNum><DisplayText>(Makitie et al. 2003)</DisplayText><record><rec-number>22</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519794285″>22</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Makitie, O.</author><author>Doria, A.</author><author>Kooh, S. W.</author><author>Cole, W. G.</author><author>Daneman, A.</author><author>Sochett, E.</author></authors></contributors><auth-address>Division of Endocrinology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8. [email protected]</auth-address><titles><title>Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets</title><secondary-title>J Clin Endocrinol Metab</secondary-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><pages>3591-7</pages><volume>88</volume><number>8</number><keywords><keyword>Age of Onset</keyword><keyword>Body Height/drug effects</keyword><keyword>Bone and Bones/diagnostic imaging</keyword><keyword>Calcitriol/blood</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Growth/*drug effects</keyword><keyword>Humans</keyword><keyword>Hypophosphatemia/blood</keyword><keyword>Hypophosphatemia, Familial/diagnostic imaging/metabolism/*therapy</keyword><keyword>Infant</keyword><keyword>Radiography</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2003</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0021-972X (Print) 0021-972X (Linking)</isbn><accession-num>12915641</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/12915641</url></related-urls></urls><electronic-resource-num>10.1210/jc.2003-030036</electronic-resource-num></record></Cite></EndNote>(Makitie et al. 2003) and side-effects including hypercalcemia, nausea, vomiting, nephrocalcinosis, secondary hyperparathyroidism, and even higher FGF23 levels can occur PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Leifheit-Nestler et al. 2017; Liu et al. 2016).
In an attempt to overcome some of the side-effects of using 1,25(OH)2D3, vitamin D analogues are frequently used in the treatment of XLH. For example, alphacalcidiol may be useful in normalising biochemical parameters such as PTH in XLH patients. However, hypercalcaemia remains a side-effect of alphacalcidiol treatment which, if sustained, can lead to vascular and other soft tissue calcification PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW5nbGFydDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW5nbGFydDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE.DATA (Linglart et al. 2014). Experimentally, Eldecalcitriol (ED71) has been shown in the mouse model for XLH (HYP mice) to improve bone mineral content and serum phosphate levels PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj
TnVtPjU4PC9SZWNOdW0+PERpc3BsYXlUZXh0PihLaWRvIGV0IGFsLiAyMDEzKTwvRGlzcGxheVRl
eHQ+PHJlY29yZD48cmVjLW51bWJlcj41ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg
YXBwPSJFTiIgZGItaWQ9Inhmd2Z4czl2MnpycGU5ZXIyYTlwd2Q5Znh2NXoydjkyd2U1ZCIgdGlt
ZXN0YW1wPSIxNTMzMDMyMTAzIj41ODwva2V5PjxrZXkgYXBwPSJFTldlYiIgZGItaWQ9IiI+MDwv
a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y
ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+S2lkbywgUy48L2F1dGhvcj48
YXV0aG9yPkthbmVrbywgSS48L2F1dGhvcj48YXV0aG9yPlRhdHN1bWksIFMuPC9hdXRob3I+PGF1
dGhvcj5TZWdhd2EsIEguPC9hdXRob3I+PGF1dGhvcj5NaXlhbW90bywgSy48L2F1dGhvcj48L2F1
dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE1vbGVjdWxh
ciBOdXRyaXRpb24sIFVuaXZlcnNpdHkgb2YgVG9rdXNoaW1hIEdyYWR1YXRlIFNjaG9vbCwgMy0x
OC0xNSBLdXJhbW90by1jaG8sIFRva3VzaGltYSwgSmFwYW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxl
cz48dGl0bGU+Vml0YW1pbiBEIGFuZCB0eXBlIElJIHNvZGl1bS1kZXBlbmRlbnQgcGhvc3BoYXRl
IGNvdHJhbnNwb3J0ZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNvbnRyaWIgTmVwaHJvbDwv
c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkNvbnRyaWIg
TmVwaHJvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjg2LTk3PC9wYWdlcz48dm9s
dW1lPjE4MDwvdm9sdW1lPjxlZGl0aW9uPjIwMTMvMDUvMDk8L2VkaXRpb24+PGtleXdvcmRzPjxr
ZXl3b3JkPkFic29ycHRpb248L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5
d29yZD5DYWxjaXRyaW9sL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2FsY2l1bSwgRGll
dGFyeS90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBLaWRuZXkgRGlz
ZWFzZS1NaW5lcmFsIGFuZCBCb25lIERpc29yZGVyL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv
cmQ+RmFtaWxpYWwgSHlwb3Bob3NwaGF0ZW1pYyBSaWNrZXRzL2RpZXQgdGhlcmFweS9tZXRhYm9s
aXNtPC9rZXl3b3JkPjxrZXl3b3JkPkZpYnJvYmxhc3QgR3Jvd3RoIEZhY3RvcnMvcGh5c2lvbG9n
eTwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Npb24gUmVndWxhdGlvbjwva2V5d29yZD48
a2V5d29yZD5HbHVjdXJvbmlkYXNlL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5z
PC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9waG9zcGhhdGVtaWEvcGh5c2lvcGF0aG9sb2d5PC9rZXl3
b3JkPjxrZXl3b3JkPkludGVzdGluYWwgQWJzb3JwdGlvbjwva2V5d29yZD48a2V5d29yZD5LaWRu
ZXkgVHVidWxlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtl
eXdvcmQ+TWljZSwgS25vY2tvdXQ8L2tleXdvcmQ+PGtleXdvcmQ+UGFyYXRoeXJvaWQgSG9ybW9u
ZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaGF0ZXMvKm1ldGFib2xpc208L2tl
eXdvcmQ+PGtleXdvcmQ+UGhvc3Bob3J1cywgRGlldGFyeS9waGFybWFjb2tpbmV0aWNzPC9rZXl3
b3JkPjxrZXl3b3JkPlJlY2VwdG9ycywgQ2FsY2l0cmlvbC9kZWZpY2llbmN5L3BoeXNpb2xvZ3k8
L2tleXdvcmQ+PGtleXdvcmQ+U29kaXVtLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlNv
ZGl1bS1QaG9zcGhhdGUgQ290cmFuc3BvcnRlciBQcm90ZWlucywgVHlwZSBJSS8qbWV0YWJvbGlz
bTwva2V5d29yZD48a2V5d29yZD5WaXRhbWluIEQvKm1ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3
b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48L2RhdGVzPjxpc2JuPjE2NjItMjc4MiAoRWxl
Y3Ryb25pYykmI3hEOzAzMDItNTE0NCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjM2
NTI1NTI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3
Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzNjUyNTUyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91
cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTU5LzAwMDM0Njc4NjwvZWxlY3Ryb25p
Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (Kido et al. 2013), however, ED-71 also causes hypercalcemia in other studies related to osteoporosis-treatment PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj
TnVtPjU4PC9SZWNOdW0+PERpc3BsYXlUZXh0PihLaWRvIGV0IGFsLiAyMDEzKTwvRGlzcGxheVRl
eHQ+PHJlY29yZD48cmVjLW51bWJlcj41ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg
YXBwPSJFTiIgZGItaWQ9Inhmd2Z4czl2MnpycGU5ZXIyYTlwd2Q5Znh2NXoydjkyd2U1ZCIgdGlt
ZXN0YW1wPSIxNTMzMDMyMTAzIj41ODwva2V5PjxrZXkgYXBwPSJFTldlYiIgZGItaWQ9IiI+MDwv
a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y
ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+S2lkbywgUy48L2F1dGhvcj48
YXV0aG9yPkthbmVrbywgSS48L2F1dGhvcj48YXV0aG9yPlRhdHN1bWksIFMuPC9hdXRob3I+PGF1
dGhvcj5TZWdhd2EsIEguPC9hdXRob3I+PGF1dGhvcj5NaXlhbW90bywgSy48L2F1dGhvcj48L2F1
dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE1vbGVjdWxh
ciBOdXRyaXRpb24sIFVuaXZlcnNpdHkgb2YgVG9rdXNoaW1hIEdyYWR1YXRlIFNjaG9vbCwgMy0x
OC0xNSBLdXJhbW90by1jaG8sIFRva3VzaGltYSwgSmFwYW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxl
cz48dGl0bGU+Vml0YW1pbiBEIGFuZCB0eXBlIElJIHNvZGl1bS1kZXBlbmRlbnQgcGhvc3BoYXRl
IGNvdHJhbnNwb3J0ZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNvbnRyaWIgTmVwaHJvbDwv
c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkNvbnRyaWIg
TmVwaHJvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjg2LTk3PC9wYWdlcz48dm9s
dW1lPjE4MDwvdm9sdW1lPjxlZGl0aW9uPjIwMTMvMDUvMDk8L2VkaXRpb24+PGtleXdvcmRzPjxr
ZXl3b3JkPkFic29ycHRpb248L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5
d29yZD5DYWxjaXRyaW9sL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2FsY2l1bSwgRGll
dGFyeS90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBLaWRuZXkgRGlz
ZWFzZS1NaW5lcmFsIGFuZCBCb25lIERpc29yZGVyL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv
cmQ+RmFtaWxpYWwgSHlwb3Bob3NwaGF0ZW1pYyBSaWNrZXRzL2RpZXQgdGhlcmFweS9tZXRhYm9s
aXNtPC9rZXl3b3JkPjxrZXl3b3JkPkZpYnJvYmxhc3QgR3Jvd3RoIEZhY3RvcnMvcGh5c2lvbG9n
eTwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Npb24gUmVndWxhdGlvbjwva2V5d29yZD48
a2V5d29yZD5HbHVjdXJvbmlkYXNlL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5z
PC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9waG9zcGhhdGVtaWEvcGh5c2lvcGF0aG9sb2d5PC9rZXl3
b3JkPjxrZXl3b3JkPkludGVzdGluYWwgQWJzb3JwdGlvbjwva2V5d29yZD48a2V5d29yZD5LaWRu
ZXkgVHVidWxlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtl
eXdvcmQ+TWljZSwgS25vY2tvdXQ8L2tleXdvcmQ+PGtleXdvcmQ+UGFyYXRoeXJvaWQgSG9ybW9u
ZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaGF0ZXMvKm1ldGFib2xpc208L2tl
eXdvcmQ+PGtleXdvcmQ+UGhvc3Bob3J1cywgRGlldGFyeS9waGFybWFjb2tpbmV0aWNzPC9rZXl3
b3JkPjxrZXl3b3JkPlJlY2VwdG9ycywgQ2FsY2l0cmlvbC9kZWZpY2llbmN5L3BoeXNpb2xvZ3k8
L2tleXdvcmQ+PGtleXdvcmQ+U29kaXVtLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlNv
ZGl1bS1QaG9zcGhhdGUgQ290cmFuc3BvcnRlciBQcm90ZWlucywgVHlwZSBJSS8qbWV0YWJvbGlz
bTwva2V5d29yZD48a2V5d29yZD5WaXRhbWluIEQvKm1ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3
b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48L2RhdGVzPjxpc2JuPjE2NjItMjc4MiAoRWxl
Y3Ryb25pYykmI3hEOzAzMDItNTE0NCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjM2
NTI1NTI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3
Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzNjUyNTUyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91
cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTU5LzAwMDM0Njc4NjwvZWxlY3Ryb25p
Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (Kido et al. 2013).
Many studies investigating vitamin D-related treatments for XLH have used the HYP mouse model as a homolog for XLH for proof-of-principle studies. The biochemical and skeletal responses to phosphate supplementation in HYP are very similar to human XLH patients and are thus a very valuable resource for researching this rare disease ADDIN EN.CITE <EndNote><Cite><Author>Eicher</Author><Year>1976</Year><RecNum>76</RecNum><DisplayText>(Eicher et al. 1976; Marie, Travers &amp; Glorieux 1981)</DisplayText><record><rec-number>76</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533032419″>76</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Eicher, E. M</author><author>Southard, J. L</author><author>Scriver, C. R</author><author>Glorieux, F. H.</author></authors></contributors><titles><title>Hypophosphatemia: Mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets</title><secondary-title>Proc Natl Acad Sci USA</secondary-title></titles><periodical><full-title>Proc Natl Acad Sci USA</full-title></periodical><pages>4667-4671</pages><volume>73</volume><number>12</number><dates><year>1976</year></dates><urls></urls></record></Cite><Cite><Author>Marie</Author><Year>1981</Year><RecNum>17</RecNum><record><rec-number>17</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519793688″>17</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P. J.</author><author>Travers, R.</author><author>Glorieux, F. H.</author></authors></contributors><titles><title>Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse</title><secondary-title>Journal of Clinical Investigation</secondary-title></titles><periodical><full-title>Journal of Clinical Investigation</full-title></periodical><pages>911-914</pages><volume>67</volume><number>3</number><dates><year>1981</year></dates><isbn>0021-9738</isbn><urls></urls><electronic-resource-num>10.1172/jci110110</electronic-resource-num></record></Cite></EndNote>(Eicher et al. 1976; Marie, Travers & Glorieux 1981). HYP mice display many of the same phenotypic traits such as hypophosphatemia, rickets, high serum alkaline phosphatase, modest hypocalcaemia, and marked reduction in bone growth and mineralisation ADDIN EN.CITE <EndNote><Cite><Author>Eicher</Author><Year>1976</Year><RecNum>76</RecNum><DisplayText>(Eicher et al. 1976; Marie, P.J, Travers, R &amp; Glorieux, F.H 1982)</DisplayText><record><rec-number>76</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533032419″>76</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Eicher, E. M</author><author>Southard, J. L</author><author>Scriver, C. R</author><author>Glorieux, F. H.</author></authors></contributors><titles><title>Hypophosphatemia: Mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets</title><secondary-title>Proc Natl Acad Sci USA</secondary-title></titles><periodical><full-title>Proc Natl Acad Sci USA</full-title></periodical><pages>4667-4671</pages><volume>73</volume><number>12</number><dates><year>1976</year></dates><urls></urls></record></Cite><Cite><Author>Marie</Author><Year>1982</Year><RecNum>16</RecNum><record><rec-number>16</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519792889″>16</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P.J</author><author>Travers, R</author><author>Glorieux, F.H</author></authors></contributors><titles><title>Bone Response to Phosphate and Vitamin D Metabolites in the Hypophosphatemic mouse model</title><secondary-title>Calcified Tissue International</secondary-title></titles><periodical><full-title>Calcified Tissue International</full-title></periodical><pages>158-164</pages><volume>34</volume><number>1</number><dates><year>1982</year></dates><urls></urls></record></Cite></EndNote>(Eicher et al. 1976; Marie, P.J, Travers, R & Glorieux, F.H 1982). FGF23 levels in HYP mice are up to 25-fold higher than in WT mice, and CYP24A1 levels are significantly elevated PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BemFtPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BemFtPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj
TnVtPjkwPC9SZWNOdW0+PERpc3BsYXlUZXh0PihBemFtIGV0IGFsLiAyMDAzKTwvRGlzcGxheVRl
eHQ+PHJlY29yZD48cmVjLW51bWJlcj45MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg
YXBwPSJFTiIgZGItaWQ9Inhmd2Z4czl2MnpycGU5ZXIyYTlwd2Q5Znh2NXoydjkyd2U1ZCIgdGlt
ZXN0YW1wPSIxNTM0MDY5MDkxIj45MDwva2V5PjxrZXkgYXBwPSJFTldlYiIgZGItaWQ9IiI+MDwv
a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y
ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QXphbSwgTi48L2F1dGhvcj48
YXV0aG9yPlpoYW5nLCBNLiBZLjwvYXV0aG9yPjxhdXRob3I+V2FuZywgWC48L2F1dGhvcj48YXV0
aG9yPlRlbmVuaG91c2UsIEguIFMuPC9hdXRob3I+PGF1dGhvcj5Qb3J0YWxlLCBBLiBBLjwvYXV0
aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2Yg
UGVkaWF0cmljcywgVW5pdmVyc2l0eSBvZiBDYWxpZm9ybmlhIFNhbiBGcmFuY2lzY28sIFNhbiBG
cmFuY2lzY28sIENhbGlmb3JuaWEgOTQxNDMsIFVTQS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0
aXRsZT5EaXNvcmRlcmVkIHJlZ3VsYXRpb24gb2YgcmVuYWwgMjUtaHlkcm94eXZpdGFtaW4gRC0x
YWxwaGEtaHlkcm94eWxhc2UgZ2VuZSBleHByZXNzaW9uIGJ5IHBob3NwaG9ydXMgaW4gWC1saW5r
ZWQgaHlwb3Bob3NwaGF0ZW1pYyAoaHlwKSBtaWNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkVu
ZG9jcmlub2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10
aXRsZT5FbmRvY3Jpbm9sb2d5PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzQ2My04
PC9wYWdlcz48dm9sdW1lPjE0NDwvdm9sdW1lPjxudW1iZXI+ODwvbnVtYmVyPjxlZGl0aW9uPjIw
MDMvMDcvMTc8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjI1LUh5ZHJveHl2aXRhbWluIEQz
IDEtYWxwaGEtSHlkcm94eWxhc2UvKmdlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8
L2tleXdvcmQ+PGtleXdvcmQ+Q3l0b2Nocm9tZSBQLTQ1MCBFbnp5bWUgU3lzdGVtL2dlbmV0aWNz
PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Np
b24gUmVndWxhdGlvbiwgRW56eW1vbG9naWMvKmRydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29y
ZD5HZW5ldGljIExpbmthZ2U8L2tleXdvcmQ+PGtleXdvcmQ+SHlwb3Bob3NwaGF0ZW1pYSwgRmFt
aWxpYWwvKmVuenltb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+S2lkbmV5Lyplbnp5bW9sb2d5PC9r
ZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5
d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+UGhvc3Bob3J1cy9ibG9v
ZC8qcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaG9ydXMsIERpZXRhcnkvYWRt
aW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlPC9rZXl3b3JkPjxrZXl3b3JkPlJOQSwgTWVzc2VuZ2Vy
L2FuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPlN0ZXJvaWQgSHlkcm94eWxhc2VzL2dlbmV0aWNz
PC9rZXl3b3JkPjxrZXl3b3JkPlZpdGFtaW4gRDMgMjQtSHlkcm94eWxhc2U8L2tleXdvcmQ+PGtl
eXdvcmQ+WCBDaHJvbW9zb21lPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDM8
L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNi
bj4wMDEzLTcyMjcgKFByaW50KSYjeEQ7MDAxMy03MjI3IChMaW5raW5nKTwvaXNibj48YWNjZXNz
aW9uLW51bT4xMjg2NTMyNjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+
aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMTI4NjUzMjY8L3VybD48L3JlbGF0
ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEyMTAvZW4uMjAwMy0w
MjU1PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==
ADDIN EN.CITE.DATA (Azam et al. 2003). Similarly to XLH patients, HYP mice display an intestinal resistance to vitamin D therapy and defective renal CYP27B1 activity ADDIN EN.CITE <EndNote><Cite><Author>Meyer</Author><Year>1996</Year><RecNum>15</RecNum><DisplayText>(Meyer, Meyer &amp; Morgan 1996)</DisplayText><record><rec-number>15</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519792619″>15</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Meyer, R.A</author><author>Meyer, M. H</author><author>Morgan, P.L</author></authors></contributors><titles><title><style face=”normal” font=”default” size=”100%”>Effects of Altered Diet on Serum levels of 1,25-Dihydroxyvitamin D and Parathyroid Hormone in X-Linked Hypophosphatemic </style><style face=”italic” font=”default” size=”100%”>(HYP and Gy) </style><style face=”normal” font=”default” size=”100%”>Mice</style></title><secondary-title>Bone</secondary-title></titles><periodical><full-title>Bone</full-title></periodical><pages>23-28</pages><volume>18</volume><number>1</number><dates><year>1996</year></dates><urls></urls></record></Cite></EndNote>(Meyer, Meyer & Morgan 1996). HYP mice have been reported to have low 1,25(OH)2D3 and 25(OH)D3 levels, and indeed, our group has also found this in recent unpublished observations.

The majority of interventions on HYP mice have tested the efficacy of either phosphate, 1,25(OH)D3, or a combination of the two. Daily injections of 1,25(OH)2D3 in HYP mice were shown to improve cortical microarchitecture and whole bone biomechanical properties PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Liu et al. 2016). The daily treatment of 1,25(OH)2D3 also led to a decrease in urine phosphate wasting despite the increasing FGF23 levels. Mice had normocalcaemia, normal PTH, and increased serum phosphate levels. The sodium-phosphate transporters in the gut were upregulated, and body weight increased. The bone growth plate and metaphyseal organisation were improved, along with the lumbar vertebral height, and trabecular structure PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Liu et al. 2016). However, 1,25(OH)2D treatment at this scale in humans would cause hypercalcaemia and nephrocalcinosis.

Only one previous study has used the inactive from of vitamin D, 25(OH)D3, to try rescue the bone phenotype ADDIN EN.CITE <EndNote><Cite><Author>Marie</Author><Year>1982</Year><RecNum>80</RecNum><DisplayText>(Marie, P. J, Travers, R &amp; Glorieux, F. H 1982)</DisplayText><record><rec-number>80</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533113679″>80</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P. J</author><author>Travers, R</author><author>Glorieux, F. H</author></authors></contributors><titles><title>Healing of bone lesions with 1, 25-dihydroxyvitamin D3 in the young X-linked hypophosphatemic male mouse</title><secondary-title>Endocrinology</secondary-title></titles><periodical><full-title>Endocrinology</full-title></periodical><pages>904-911</pages><volume>111</volume><number>3</number><dates><year>1982</year></dates><isbn>0013-7227</isbn><urls><related-urls><url><style face=”underline” font=”default” size=”100%”>https://academic.oup.com/endo/article-abstract/111/3/904/2591271?redirectedFrom=fulltext</style></url></related-urls></urls></record></Cite></EndNote>(Marie, P. J, Travers, R & Glorieux, F. H 1982). Marie et al infused a relatively low dose of 25(OH)D3 into HYP mice over a 3 week period, in addition to phosphate salts in the drinking water. While 25(OH)D3 levels were shown to marginally improve, the underminerlised bone persisted. This suggested to the authors that there was a specific bone cell resistance to mineral and/or hormonal treatment ADDIN EN.CITE <EndNote><Cite><Author>Marie</Author><Year>1982</Year><RecNum>16</RecNum><DisplayText>(Marie, P.J, Travers, R &amp; Glorieux, F.H 1982)</DisplayText><record><rec-number>16</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519792889″>16</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P.J</author><author>Travers, R</author><author>Glorieux, F.H</author></authors></contributors><titles><title>Bone Response to Phosphate and Vitamin D Metabolites in the Hypophosphatemic mouse model</title><secondary-title>Calcified Tissue International</secondary-title></titles><periodical><full-title>Calcified Tissue International</full-title></periodical><pages>158-164</pages><volume>34</volume><number>1</number><dates><year>1982</year></dates><urls></urls></record></Cite></EndNote>(Marie, P.J, Travers, R & Glorieux, F.H 1982). While this conclusion may be true, no further investigations have been performed to elevate 25(OH)D to levels that, more recently, have shown to improve bone mineralisation in other settings. For example, 20,000IU/kg of vitamin D fed to Wild Type (WT) mice resulted in increased bone mineralisation and stronger bones without causing hypercalcemia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxsaWFtc29uPC9BdXRob3I+PFllYXI+MjAxNzwvWWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxsaWFtc29uPC9BdXRob3I+PFllYXI+MjAxNzwvWWVh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ADDIN EN.CITE.DATA (Williamson et al. 2017).

The role of vitamin D catabolism in XLH
CYP24A1 is the sole enzyme involved in the catabolism of vitamin D. While the classical view is that CYP24A1 limits the tissue activity of 1,25(OH)2D, renal CYP24A1 activity has been shown to regulate circulating 1,25(OH)2D levels which also impacts tissue-level activity as well PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmRlcnNvbjwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmRlcnNvbjwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+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 EN.CITE.DATA (Anderson et al. 2004). Furthermore, in bone CYP24A1 activity has been shown to be regulated independently of circulating 1,25(OH)2D levels, indicating that autocrine regulation of 1,25(OH)2D activity in bone is independent of renal vitamin D metabolism regulation ADDIN EN.CITE <EndNote><Cite><Author>Anderson</Author><Year>2005</Year><RecNum>100</RecNum><DisplayText>(Anderson et al. 2005)</DisplayText><record><rec-number>100</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1537164458″>100</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Anderson, P. H.</author><author>O&apos;Loughlin, P. D.</author><author>May, B. K.</author><author>Morris, H. A.</author></authors></contributors><auth-address>Endocrine Bone Research Laboratory, Hanson Institute, Adelaide, SA, Australia. [email protected]</auth-address><titles><title>Modulation of CYP27B1 and CYP24 mRNA expression in bone is independent of circulating 1,25(OH)2D3 levels</title><secondary-title>Bone</secondary-title></titles><periodical><full-title>Bone</full-title></periodical><pages>654-62</pages><volume>36</volume><number>4</number><edition>2005/03/23</edition><keywords><keyword>25-Hydroxyvitamin D3 1-alpha-Hydroxylase/*genetics</keyword><keyword>Animals</keyword><keyword>Bone and Bones/anatomy &amp; histology/*enzymology</keyword><keyword>Calcitriol/*blood</keyword><keyword>Cytochrome P-450 Enzyme System/*genetics</keyword><keyword>Female</keyword><keyword>Kidney/enzymology</keyword><keyword>RNA, Messenger/*genetics</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword><keyword>Receptors, Calcitriol/genetics</keyword><keyword>Reverse Transcriptase Polymerase Chain Reaction</keyword><keyword>Steroid Hydroxylases/*genetics</keyword><keyword>Vitamin D3 24-Hydroxylase</keyword></keywords><dates><year>2005</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>8756-3282 (Print) 1873-2763 (Linking)</isbn><accession-num>15781002</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/15781002</url></related-urls></urls><electronic-resource-num>10.1016/j.bone.2005.01.012</electronic-resource-num></record></Cite></EndNote>(Anderson et al. 2005). We have recently also demonstrated that the genetic deletion of CYP24A1 in osteocytes using Cre-lox technology, increases bone volume in young mice suggesting that the CYP24A1 in osteocytes plays an inhibitory role on bone mineralisation (Barratt et al, in preparation).
In Hyp mice, renal CYP24A1 levels have been shown to be 2-fold higher in HYP mice PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BemFtPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BemFtPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj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==
ADDIN EN.CITE.DATA (Azam et al. 2003) which contributes to lower circulating 1,25(OH)2D levels. No investigations have yet been performed to demonstrate whether osteocytic CYP24A1 levels are in increased in Hyp mice. However, it is unclear whether the bones of HYP mice have aberrantly high CYP24A1, which would frustrate the anabolic activities of 1,25(OH)2D. It is worth noting however, that low phosphate levels may directly contribute to the high expression of CYP24A1, in osteocytes at least, given that decreasing phosphate levels in media of the osteocyte cell line, IDG-SW3, enhances the induction of Cyp24a1 by 1,25(OH)2D PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5JdG88L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5JdG88L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Ito et al. 2013). Furthermore, HYP primary osteocytes exposed to 1,25(OH)2D do not induce mRNA levels for vitamin D responsive genes such as VDR or Fgf23 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaXlhZ2F3YTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaXlhZ2F3YTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE.DATA (Miyagawa et al. 2014), perhaps suggesting that excessive CYP24A1 catabolises 1,25(OH)2D. However, the authors of this study did not directly measure CYP24A1 or 1,25(OH)2D clearance (Prof T. Michigami, personal communications). Regardless, these data suggest that Cyp24a1 activity in bone, possibly osteoblasts, osteocytes or chondrocytes during phosphate wasting disorders, may reduce 1,25D activity in bone, resulting in under-mineralisation.
A recent key study in investigating the role of CYP24A1 in HYP mice was performed by crossing the global CYP24A1-knockout mice with HYP mice. The hypothesis was that the absence of CYP24A1 would elevate circulating 1,25(OH)2D levels and contribute to the healing of the XLH bone phenotype PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Bai et al. 2016). To the surprise of the authors, the absence of CYP24A1 resulted in the complete prevention of growth and mineralisation disorder in HYP mice PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Bai et al. 2016). Interestingly, while growth plate and cortical bone mineral was restored, the key biochemical indices of HYP disorder, namely hypophosphatemia and low 1,25(OH)2D levels, remained low and unchanged PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Bai et al. 2016). These exciting data suggest that the current therapy of correcting blood phosphate and circulating 1,25(OH)2D is not essential to normalise bone health in XLH. Furthermore, these data suggest that CYP24A1 deletion in tissues other than the kidney, play a major role in allowing normal bone mineral levels. Given the evidence for the role of CYP24A1 in bone homeostasis, a key tissue to investigate further is the bone with respect to CYP24A1 and its role in XLH.

RESEARCH DESIGN:
Aim 1: To determine whether raising circulating 25-hydroxyvitamin D (25D) levels heal the bone in Hyp mice.

Rationale: The disorder of XLH, was previously known as vitamin D-resistant rickets owing to the fact the renal conversion of 25(OH)D3 to 1,25(OH)D3 was impeded by FGF23 ADDIN EN.CITE <EndNote><Cite><Author>Saito</Author><Year>2009</Year><RecNum>28</RecNum><DisplayText>(Saito &amp; Fukumoto 2009)</DisplayText><record><rec-number>28</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519884606″>28</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Saito, T.</author><author>Fukumoto, S.</author></authors></contributors><auth-address>Department of Pediatrics, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.</auth-address><titles><title>Fibroblast Growth Factor 23 (FGF23) and Disorders of Phosphate Metabolism</title><secondary-title>Int J Pediatr Endocrinol</secondary-title></titles><periodical><full-title>Int J Pediatr Endocrinol</full-title></periodical><pages>496514</pages><volume>2009</volume><dates><year>2009</year></dates><isbn>1687-9856 (Electronic) 1687-9848 (Linking)</isbn><accession-num>19956747</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/19956747</url></related-urls></urls><custom2>PMC2775677</custom2><electronic-resource-num>10.1155/2009/496514</electronic-resource-num></record></Cite></EndNote>(Saito & Fukumoto 2009). We know that bone is a major site for local synthesis and activity of 1,25(OH)D3 and is dependent on the circulating supply of 25(OH)D3 ADDIN EN.CITE <EndNote><Cite><Author>Anderson</Author><Year>2017</Year><RecNum>94</RecNum><DisplayText>(Anderson 2017)</DisplayText><record><rec-number>94</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1534470997″>94</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Anderson, P. H.</author></authors></contributors><auth-address>Musculoskeletal Biology Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, 5001, Australia. [email protected]</auth-address><titles><title>Vitamin D Activity and Metabolism in Bone</title><secondary-title>Curr Osteoporos Rep</secondary-title></titles><periodical><full-title>Curr Osteoporos Rep</full-title></periodical><pages>443-449</pages><volume>15</volume><number>5</number><edition>2017/08/16</edition><keywords><keyword>25-Hydroxyvitamin D3 1-alpha-Hydroxylase/*metabolism</keyword><keyword>Autocrine Communication</keyword><keyword>Bone Resorption/metabolism</keyword><keyword>Bone and Bones/*metabolism</keyword><keyword>Calcification, Physiologic/physiology</keyword><keyword>Fracture Healing/physiology</keyword><keyword>Humans</keyword><keyword>Receptors, Calcitriol/*metabolism</keyword><keyword>Vitamin D/*analogs &amp; derivatives/metabolism</keyword><keyword>Vitamin D3 24-Hydroxylase/*metabolism</keyword><keyword>Cyp24a1</keyword><keyword>Cyp27b1</keyword><keyword>Mineralisation</keyword><keyword>Osteoblasts</keyword><keyword>Vitamin D</keyword><keyword>Vitamin D receptor</keyword></keywords><dates><year>2017</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1544-2241 (Electronic) 1544-1873 (Linking)</isbn><accession-num>28808890</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/28808890</url></related-urls></urls><electronic-resource-num>10.1007/s11914-017-0394-8</electronic-resource-num></record></Cite></EndNote>(Anderson 2017). There have been no previous studies to examine whether raising 25(OH)D3 to high levels through dietary vitamin D administration can heal the bone phenotype more easily than 1,25(OH)D3. Thus, it is valuable to assess whether the HYP bone can be healed through raising the serum 25(OH)D levels either by dietary vitamin D supplementation or direct infusion of 25(OH)D.

Model 1: Male HYP (XHypY) mice will be supplemented with vitamin D from 3 weeks of age until 12 weeks of age. Mice (n=12/grp) will receive diets containing 1000 IU/kg (standard) or 20,000IU/kg of vitamin D plus either 0.625% phosphorus (standard) or 1.25% phosphorus (high). These levels of vitamin D should significantly raise 25(OH)D3 levels to an approximate maximum of 200 nmol/L without causing direct activation of the VDR ADDIN EN.CITE <EndNote><Cite><Author>Rowling</Author><Year>2007</Year><RecNum>6750</RecNum><DisplayText>(Rowling, M. J. et al. 2007)</DisplayText><record><rec-number>6750</rec-number><foreign-keys><key app=”EN” db-id=”5ardrpxr60pvfnef52axpsxpptazw02s9pvw” timestamp=”1253599895″>6750</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Rowling, M. J.</author><author>Gliniak, C.</author><author>Welsh, J.</author><author>Fleet, J. C.</author></authors></contributors><auth-address>Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556 4Interdepartmental Nutrition Program and Department of Foods and Nutrition, Purdue University, West Lafayette, IN 47906.</auth-address><titles><title>High Dietary Vitamin D Prevents Hypocalcemia and Osteomalacia in CYP27B1 Knockout Mice</title><secondary-title>J Nutr</secondary-title></titles><pages>2608-15</pages><volume>137</volume><number>12</number><dates><year>2007</year><pub-dates><date>Dec</date></pub-dates></dates><accession-num>18029472</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=18029472</url></related-urls></urls></record></Cite></EndNote>(Rowling, M. J. et al. 2007).

Model 2; Male HYP (XHypY) mice will be fed a standard level of phosphorus from 3 weeks of age until 8 weeks of age. At 4 weeks of age, mice will undergo minor surgery to insert a mini osmotic pump (Alzet 1004) subcutaneously containing 25(OH)D3 (100ng or 200ng/day), or saline, at a constant rate over a 4 week period.
At time of death, we will collect tissues and employ our suite of established analyses described in previous publications PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmRlcnNvbjwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmRlcnNvbjwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+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=
ADDIN EN.CITE.DATA (Anderson et al. 2005; Anderson et al. 2008; Chiang et al. 2009). Biochemical analyses: serum levels of calcium, phosphate, ALP (Kone Chemistry Analyser), 25(OH)D3 and 1,25(OH)D3 (LC-MS/MS), PTH, and intact FGF23 (commercially available ELISA assays). Ex-vivo micro-CT analyses: For Model 1, femoral and vertebral scans will be performs as per laboratory SOPs. This provides a non-destructive 3D image of the inner bone structure and allows for evaluation of the treatment on bone health. Regions of interest (ROI) will be adjusted based on the average femur length for each of the groups. In vivo micro-CT analyses: For Model 2, 2 weeks post-surgery (6 weeks of age), mice will be anaesthetised for a lower-leg micro-CT scan (Skyscan 1276). This provides a non-destructive 3D image of the inner bone structure and allows a mid-treatment evaluation of the treatment on bone health. Tissue histology and histomorphometric analyses: To evaluate mineralisation, sections of the left femur (after microCT scanning) will be embedded in methylmethacrylate before sectioning. Histomorphometry will use Osteomeasure (Osteometrics), in accordance to criteria of the American Society of Bone and Mineral Research ADDIN EN.CITE <EndNote><Cite><Author>Dempster</Author><Year>2013</Year><RecNum>93</RecNum><DisplayText>(Dempster et al. 2013)</DisplayText><record><rec-number>93</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1534470947″>93</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Dempster, D. W.</author><author>Compston, J. E.</author><author>Drezner, M. K.</author><author>Glorieux, F. H.</author><author>Kanis, J. A.</author><author>Malluche, H.</author><author>Meunier, P. J.</author><author>Ott, S. M.</author><author>Recker, R. R.</author><author>Parfitt, A. M.</author></authors></contributors><auth-address>Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, NY, USA. [email protected]</auth-address><titles><title>Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee</title><secondary-title>J Bone Miner Res</secondary-title></titles><periodical><full-title>J Bone Miner Res</full-title></periodical><pages>2-17</pages><volume>28</volume><number>1</number><edition>2012/12/01</edition><keywords><keyword>Animals</keyword><keyword>Bone and Bones/*anatomy &amp; histology</keyword><keyword>Guidelines as Topic</keyword><keyword>Humans</keyword><keyword>Reference Standards</keyword><keyword>*Research Report</keyword><keyword>*Terminology as Topic</keyword></keywords><dates><year>2013</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1523-4681 (Electronic) 0884-0431 (Linking)</isbn><accession-num>23197339</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/23197339</url></related-urls></urls><custom2>PMC3672237</custom2><electronic-resource-num>10.1002/jbmr.1805</electronic-resource-num></record></Cite></EndNote>(Dempster et al. 2013), and include measures of bone formation (dual fluorochrome labelling prior to death), osteoid volume and growth plate height (Massons’-Goldner’s Modified Trichrome), osteoblast surface (toluidine blue staining), and osteoclasts (TRAP stain). Messenger RNA analyses: Soft tissues will be snap frozen and RNA extracted using the TRIZOL RNA isolation protocol. cDNA will be synthesised for the purpose of RT PCR’s. Relative expression of CYP24A1, CYP27B1, NaPi2a, NaPi2c, CYP2R1 and CYP24A1 will be reported.

Outcomes This study is a necessary dietary intervention for HYP mice that frankly should have been done years ago. It will assess if there is resistance to vitamin D synthesis and activity in the bone of HYP mice, be it due to excessive FGF23 or another factor, even with high circulating levels of 25(OH)D and dietary phosphate supplementation.

Aim 2: To determine whether raising osteocyte levels of active vitamin D (1,25(OH)2D) heals the bone of Hyp mice.

Rationale: As discussed above, global deletion of CYP24A1 heals the under-mineralised and disturbed growth plate phenotype in HYP mice. This occurs despite the persistence of hypophosphataemia and an even lower serum 1,25(OH)D levels PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Bai et al. 2016). These data demonstrate that low serum phosphate and low circulating 1,25D levels are not primarily responsible for the under-mineralisation. While strongly suggestive, the limitation of this study is the inability to definitively implicate bone CYP24A1. The two most likely candidate cell-types in bone that are responsible for the HYP bone phenotype are osteocytes or chondrocytes. Both cell-types have been shown to produce FGF23, control phosphate homeostasis, and are involved in process of bone formation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXN1eWFtYTwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXN1eWFtYTwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+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 EN.CITE.DATA (Masuyama et al. 2006). Thus, to determine whether abrogating Cyp24a1 activity in bone improves the bone phenotype of the HYP mice, conditional knockout mouse models are required. We will utilise Cre-lox systems to delete Cyp24a1 in osteocytes. We have previously created the osteocyte-specific CYP24A1KO mice. These mice will be crossed with HYP mice to determine whether the absence of Cyp24a1 activity in either osteoblast/osteocytes or chondrocytes in HYP mice is capable of promoting mineralisation and overcoming bone under-mineralisation.

Model: Our team has previously created the floxed Cyp24a1 (Cyp24a1flox/+) and OcyCYP24KO (OcyCyp24a1-/-) mouse models. Male HYP mice are far less virile that the females so generation of a HYP mouse in which Cyp24a1 has been specifically deleted in osteocytes (HYP/OcyCyp24a1-/-) requires a particular breeding strategy. Heterozygous female HYP (XXHyp) will be crossed with Cyp24a1flox/flox males to obtain HYP/Cyp24a1flox/+ double heterozygous females. Then HYP/Cyp24a1flox/+ females will be crossed with Cyp24a1flox/flox males to generate HYP/Cyp24a1flox/flox females. Finally, HYP/Cyp24a1flox/flox females will be crossed with OcyCyp24a1-/+ males to obtain the osteoblast/osteocyte-specific deletion of Cyp24a1 in HYP mice. Studies will include the following four genotypes: Cyp24a1flox/+ (wild-type equivalent) control, OcyCyp24a1-/-, HYP (XHypY), and compound HYP/OcyCyp24a1-/- male littermates as well as Cyp24a1flox/- and HYP/Cyp24a1flox/- male mice.

Male HYP (XHypY) mice will be supplemented with vitamin D from 3 weeks of age until 12 weeks of age (as in Aim 1, Model 1), and infused with 25(OH)D (as in Aim 1, Model 2).
At time of death, analyses will include Biochemical analyses, ex-vivo micro-CT analyses, in vivo micro-CT analyses, tissue histology and histomorphometric analyses and messenger RNA analyses as described in Aim 1.

Outcomes: Central to the hypothesis of this project is whether the absence of CYP24A1 activity within osteoblasts/osteocytes as well as chondrocytes enhances healing of bone in HYP mice, despite their elevated levels of FGF23. Examining HYP/conditional CYP24A1KO mice in the context of 25(OH)D supplementation, phosphorus supplementation and 1,25(OH)2D administration will reveal the importance of raised 1,25D within the key bone cell types in this context of healing HYP bone. As well, using definitive in vitro cell models will determine whether the absence of osteoblastic/osteocytic or chondrocytic Cyp24a1 activity alters differentiation and/or apoptosis of HYP cells independently of confounding factors that could occur in the in vivo studies. At the same time these in vitro studies will seek to establish whether key players in inhibiting mineralisation (such as ASARM peptides and sclerostin) are modulated by vitamin D, phosphate and/or CYP24A1 deletion. These studies will provide important insights into targeting CYP24A1 activity in bone in the condition of XLH.

.

REFERENCES:
ADDIN EN.REFLIST Anderson, PH, O’Loughlin, PD, May, BK & Morris, HA 2004, ‘Determinants of circulating 1,25-dihydroxyvitamin D3 levels: the role of renal synthesis and catabolism of vitamin D’, J Steroid Biochem Mol Biol, vol. 89-90, no. 1-5, May, pp. 111-113.

Anderson, PH, O’Loughlin, PD, May, BK & Morris, HA 2005, ‘Modulation of CYP27B1 and CYP24 mRNA expression in bone is independent of circulating 1,25(OH)2D3 levels’, Bone, vol. 36, no. 4, Apr, pp. 654-662.

Anderson, PH, Sawyer, RK, Moore, AJ, May, BK, O’Loughlin, PD & Morris, HA 2008, ‘Vitamin D depletion induces RANKL-mediated osteoclastogenesis and bone loss in a rodent model’, Journal of Bone and Mineral Research, vol. 23, no. 11, Nov, pp. 1789-1797.

Anderson, PH 2017, ‘Vitamin D Activity and Metabolism in Bone’, Curr Osteoporos Rep, vol. 15, no. 5, Oct, pp. 443-449.

Azam, N, Zhang, MY, Wang, X, Tenenhouse, HS & Portale, AA 2003, ‘Disordered regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase gene expression by phosphorus in X-linked hypophosphatemic (hyp) mice’, Endocrinology, vol. 144, no. 8, Aug, pp. 3463-3468.

Bai, X, Miao, D, Xiao, S, Qiu, D, St-Arnaud, R, Petkovich, M, Gupta, A, Goltzman, D & Karaplis, AC 2016, ‘CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders’, J Clin Invest, vol. 126, no. 2, Feb, pp. 667-680.

Bowe, AE, Finnegan, R, Jan de Beur, SM, Cho, J, Levine, MA, Kumar, R & Schiavi, SC 2001, ‘FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate’, Biochem Biophys Res Commun, vol. 284, no. 4, Jun 22, pp. 977-981.

Carpenter, TO, Imel, EA, Holm, IA, Jan de Beur, SM & Insogna, KL 2011, ‘A clinician’s guide to X-linked hypophosphatemia’, J Bone Miner Res, vol. 26, no. 7, Jul, pp. 1381-1388.

Che, H, Roux, C, Etcheto, A, Rothenbuhler, A, Kamenicky, P, Linglart, A & Briot, K 2016, ‘Impaired quality of life in adults with X-linked hypophosphatemia and skeletal symptoms’, Eur J Endocrinol, vol. 174, no. 3, Mar, pp. 325-333.

Chiang, C, Chiu, M, Moore, AJ, Anderson, PH, Ghasem-Zadeh, A, McManus, JF, Ma, C, Seeman, E, Clemens, TL, Morris, HA, Zajac, JD & Davey, RA 2009, ‘Mineralization and bone resorption are regulated by the androgen receptor in male mice’, J Bone Miner Res, vol. 24, no. 4, Apr, pp. 621-631.

De Menezes Filho, H, De Castro, LCG & Damiani, D 2006, ‘Hypophosphatemic Rickets and Osteomalacia’, vol. 50, no. 4.

Dempster, DW, Compston, JE, Drezner, MK, Glorieux, FH, Kanis, JA, Malluche, H, Meunier, PJ, Ott, SM, Recker, RR & Parfitt, AM 2013, ‘Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee’, J Bone Miner Res, vol. 28, no. 1, Jan, pp. 2-17.

Eicher, EM, Southard, JL, Scriver, CR & Glorieux, FH 1976, ‘Hypophosphatemia: Mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets’, Proc Natl Acad Sci USA, vol. 73, no. 12, pp. 4667-4671.

Erben, RG 2017, ‘Pleiotropic Actions of FGF23’, Toxicol Pathol, vol. 45, no. 7, Oct, pp. 904-910.

Foster, BL, Nagatomo, KJ, Nociti, FH, Jr., Fong, H, Dunn, D, Tran, AB, Wang, W, Narisawa, S, Millan, JL & Somerman, MJ 2012, ‘Central role of pyrophosphate in acellular cementum formation’, PLoS One, vol. 7, no. 6, p. e38393.

Fuente, R, Gil-Pena, H, Claramunt-Taberner, D, Hernandez, O, Fernandez-Iglesias, A, Alonso-Duran, L, Rodriguez-Rubio, E & Santos, F 2017, ‘X-linked hypophosphatemia and growth’, Rev Endocr Metab Disord, vol. 18, no. 1, Mar, pp. 107-115.

Fuente, R, Gil-Pena, H, Claramunt-Taberner, D, Hernandez-Frias, O, Fernandez-Iglesias, A, Hermida-Prado, F, Anes-Gonzalez, G, Rubio-Aliaga, I, Lopez, JM & Santos, F 2018, ‘Marked alterations in the structure, dynamics and maturation of growth plate likely explain growth retardation and bone deformities of young Hyp mice’, Bone, vol. 116, Aug 8, pp. 187-195.

Harmey, D, Hessle, L, Narisawa, S, Johnson, KA, Terkeltaub, R & Millán, JL 2004, ‘Concerted Regulation of Inorganic Pyrophosphate and Osteopontin by Akp2, Enpp1, and Ank’, The American Journal of Pathology, vol. 164, no. 4, pp. 1199-1209.

Henry, HL 2011, ‘Regulation of vitamin D metabolism’, Best Pract Res Clin Endocrinol Metab, vol. 25, no. 4, Aug, pp. 531-541.

Ito, N, Findlay, DM, Anderson, PH, Bonewald, LF & Atkins, GJ 2013, ‘Extracellular phosphate modulates the effect of 1alpha,25-dihydroxy vitamin D3 (1,25D) on osteocyte like cells’, J Steroid Biochem Mol Biol, vol. 136, Jul, pp. 183-186.

Kido, S, Kaneko, I, Tatsumi, S, Segawa, H & Miyamoto, K 2013, ‘Vitamin D and type II sodium-dependent phosphate cotransporters’, Contrib Nephrol, vol. 180, pp. 86-97.

Ko, FC, Martins, JS, Reddy, P, Bragdon, B, Hussein, AI, Gerstenfeld, LC & Demay, MB 2016, ‘Acute Phosphate Restriction Impairs Bone Formation and Increases Marrow Adipose Tissue in Growing Mice’, J Bone Miner Res, vol. 31, no. 12, Dec, pp. 2204-2214.

Lee, JY & Imel, EA 2013, ‘The Changing Face of Hypophosphatemic Disorders in the FGF-23 Era’, Paediatr Endocrinol Rev., vol. 10, pp. 367-379.

Leifheit-Nestler, M, Kucka, J, Yoshizawa, E, Behets, G, D’Haese, P, Bergen, C, Meier, M, Fischer, DC & Haffner, D 2017, ‘Comparison of calcimimetic R568 and calcitriol in mineral homeostasis in the Hyp mouse, a murine homolog of X-linked hypophosphatemia’, Bone, vol. 103, Oct, pp. 224-232.

Linglart, A, Biosse-Duplan, M, Briot, K, Chaussain, C, Esterle, L, Guillaume-Czitrom, S, Kamenicky, P, Nevoux, J, Prie, D, Rothenbuhler, A, Wicart, P & Harvengt, P 2014, ‘Therapeutic management of hypophosphatemic rickets from infancy to adulthood’, Endocr Connect, vol. 3, no. 1, pp. R13-30.

Liu, ES, Martins, JS, Raimann, A, Chae, BT, Brooks, DJ, Jorgetti, V, Bouxsein, ML & Demay, MB 2016, ‘1,25-Dihydroxyvitamin D Alone Improves Skeletal Growth, Microarchitecture, and Strength in a Murine Model of XLH, Despite Enhanced FGF23 Expression’, J Bone Miner Res, vol. 31, no. 5, May, pp. 929-939.

Makitie, O, Doria, A, Kooh, SW, Cole, WG, Daneman, A & Sochett, E 2003, ‘Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets’, J Clin Endocrinol Metab, vol. 88, no. 8, Aug, pp. 3591-3597.

Marie, PJ, Travers, R & Glorieux, FH 1981, ‘Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse’, Journal of Clinical Investigation, vol. 67, no. 3, pp. 911-914.

Marie, PJ, Travers, R & Glorieux, FH 1982, ‘Bone Response to Phosphate and Vitamin D Metabolites in the Hypophosphatemic mouse model’, Calcified Tissue International, vol. 34, no. 1, pp. 158-164.

Marie, PJ, Travers, R & Glorieux, FH 1982, ‘Healing of bone lesions with 1, 25-dihydroxyvitamin D3 in the young X-linked hypophosphatemic male mouse’, Endocrinology, vol. 111, no. 3, pp. 904-911.

Masuyama, R, Stockmans, I, Torrekens, S, Van Looveren, R, Maes, C, Carmeliet, P, Bouillon, R & Carmeliet, G 2006, ‘Vitamin D receptor in chondrocytes promotes osteoclastogenesis and regulates FGF23 production in osteoblasts’, J Clin Invest, vol. 116, no. 12, Dec, pp. 3150-3159.

Meyer, RA, Meyer, MH & Morgan, PL 1996, ‘Effects of Altered Diet on Serum levels of 1,25-Dihydroxyvitamin D and Parathyroid Hormone in X-Linked Hypophosphatemic (HYP and Gy) Mice’, Bone, vol. 18, no. 1, pp. 23-28.

Millan, JL 2013, ‘The role of phosphatases in the initiation of skeletal mineralization’, Calcif Tissue Int, vol. 93, no. 4, Oct, pp. 299-306.

Miyagawa, K, Yamazaki, M, Kawai, M, Nishino, J, Koshimizu, T, Ohata, Y, Tachikawa, K, Mikuni-Takagaki, Y, Kogo, M, Ozono, K & Michigami, T 2014, ‘Dysregulated gene expression in the primary osteoblasts and osteocytes isolated from hypophosphatemic Hyp mice’, PLoS One, vol. 9, no. 4, p. e93840.

Murali, SK, Andrukhova, O, Clinkenbeard, EL, White, KE & Erben, RG 2016, ‘Excessive Osteocytic Fgf23 Secretion Contributes to Pyrophosphate Accumulation and Mineralization Defect in Hyp Mice’, PLoS Biol, vol. 14, no. 4, Apr, p. e1002427.

Pharmaceutical, U 2018, Burosumab for XLH, <https://www.ultragenyx.com/pipeline/krn23-xlh/>.

Portale, AA, Perwad, F & Miller, WL 2012, ‘Rickets Due to Hereditary Abnormalities of Vitamin D Synthesis or Action’, Pediatric Bone, pp. 679-698.

Razzaque, MS & Lanske, B 2007, ‘The emerging role of the fibroblast growth factor-23-klotho axis in renal regulation of phosphate homeostasis’, J Endocrinol, vol. 194, no. 1, Jul, pp. 1-10.

Roizen, JD, Li, D, O’Lear, L, Javaid, MK, Shaw, NJ, Ebeling, PR, Nguyen, HH, Rodda, CP, Thummel, KE, Thacher, TD, Hakonarson, H & Levine, MA 2018, ‘CYP3A4 mutation causes vitamin D-dependent rickets type 3’, J Clin Invest, vol. 128, no. 5, May 1, pp. 1913-1918.

Rowling, MJ, Gliniak, C, Welsh, J & Fleet, JC 2007, ‘High dietary vitamin D prevents hypocalcemia and osteomalacia in CYP27B1 knockout mice’, The Journal of nutrition, vol. 137, no. 12, pp. 2608-2615.

Rowling, MJ, Gliniak, C, Welsh, J & Fleet, JC 2007, ‘High Dietary Vitamin D Prevents Hypocalcemia and Osteomalacia in CYP27B1 Knockout Mice’, J Nutr, vol. 137, no. 12, Dec, pp. 2608-2615.

Sabbagh, Y, Carpenter, TO & Demay, MB 2005, ‘Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes’, Proc Natl Acad Sci U S A, vol. 102, no. 27, Jul 5, pp. 9637-9642.

Saito, T & Fukumoto, S 2009, ‘Fibroblast Growth Factor 23 (FGF23) and Disorders of Phosphate Metabolism’, Int J Pediatr Endocrinol, vol. 2009, p. 496514.

Tenenhouse, HS & Jones, G 1990, ‘Abnormal Regulation of Renal Vitamin D Catabolism by Dietary Phosphate in Murine X-linked Hypophosphatemic Rickets’, J Clin. Invest., vol. 85, pp. 1450-1455.

Vieth, R 1999, ‘Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety’, American Journal of Clinical Nutrition, vol. 69, no. 5, pp. 842-856.

Williamson, L, Hayes, A, Hanson, ED, Pivonka, P, Sims, NA & Gooi, JH 2017, ‘High dose dietary vitamin D3 increases bone mass and strength in mice’, Bone Rep, vol. 6, Jun, pp. 44-50.

GANTT CHART AND PLANNED PUBLICATIONS:
2018 2019 2020
Tasks/
Milestones M A M J J A S O N D J F M A M J J A S O N D J F M
Ethics approval process                                                  
RESA ‘Continuing to Completing’ series                                                  
Literature review                                                  
Animal research Aim 1                                                  
Data analysis Aim 1                                                  
Write up Aim 1                                                  
Animal research Aim 2                                                  
Data analysis Aim 2                                                  
Write up Aim 2                                                  
Submission                                                  

Impact of Vitamin D Therapy in treating
X-linked hypophosphatemic rickets
Kate Barratt
Research Proposal
For the degree of Masters by Research (Medical Science)
Supervisors
Associate Professor Paul Anderson
Professor Gerald Atkins
Professor Howard Morris

OUTLINE:
X-Linked HypohposphatemicHypophosphatemic (XLH) Rickets is a rare hereditary disorder that was commonly referred to as “Vitamin D Resistant Rickets.”that is difficult to treat without significant side-effects. XLH, is caused by a mutation on in the osteocyte genethe, phosphate-regulating endopeptidase homolog, X-linked (PHEX), which gene, and the pathophysiology of this disease presents soon after birth. This PHEX mutation causes the impaired cleavage and accumulation of prevents the breakdown of Fibroblast Growth Factor 23 (FGF23) and thus the effects of excessive FGF23 are seen. Elevated FGF23 levels in XLH causes excessive renal excretion of pPhosphate leading to hypophosphatemia, and low circulating active vitamin D (1,25(OH)2D) levels due to both inhibited synthesis and excessive catabolism of vitamin D. It has been long thought that disturbed renal metabolism of vitamin D is major contributor to the development of wasting and hyphosphaemia,undermineralised bone, or rickets elevated PTH and CYP24a1, low circulating vitamin D, bone pain, spontaneous fractures, hearing loss, dental abscess, and osteomalacia develop in the first few years of life. However, recent evidence suggest that Vitamin D and phosphate supplementation are commonly used to attempt to normalise serum biochemistry and the rachitic bone phenotype. More recently FGF23 antibodies and vitamin D analogues have been used in isolation, or in conjunction, with vitamin supplementation to improve outcomes. All of these current therapies are inefficient at treating this disease without causing severe side effects such as hypercalcaemia and nephrocalcinosis.Our team is researching the effects of elevated FGF23 on the HYP skeleton and possible alternatives for therapies. I will be concentrating on the use of dietary vitamin supplementation, infusion of inactive vitamin D, and inhibition of the vitamin D catabolising enzyme, CYP24a1.The murine homolog for XLH, HYP, will be used for the purposes of in vitro analyses. (a) local metabolism of 1,25(OH)2D in bone has an independent and critical role for bone mineralisation (b) that the inhibition of vitamin D catabolism in disorders of rickets due to FGF23 excess, induces the near-complete healing of rickets without the need to lower FGF23 levels nor rescue the hypophosphatemia. These data, and the importance of finding effective treatments for XLH provide great importance for investigating the following hypothesis and aims:Hypothesis: Raising active vitamin D (1,25D) levels within the bone and/or the intestine (via preventing catabolism) prevents rickets in the Hyp mouse model (the mouse homolog for the disorder of XLH) by increasing mineralisation.Aim 1: To determine whether raising circulating 25-hydroxyvitamin D (25D) levels heal the bone in Hyp mice.Aim 2: To determine whether raising osteocyte levels of active vitamin D (1,25(OH)2D) heals the bone of Hyp mice.LITERATURE REVIEW:
416623574295Figure 1: Bone deformities in a severe case of XLH0Figure 1: Bone deformities in a severe case of XLHPrevalence and impact of X-linked Hypophosphatemic Rickets: X-Linked Hypophosphatemia (XLH) is a rare genetic disorder, affecting 1 in 20,000 individuals ADDIN EN.CITE <EndNote><Cite><Author>Azam</Author><Year>2003</Year><RecNum>4275</RecNum><DisplayText>(Azam et al. 2003)</DisplayText><record><rec-number>4275</rec-number><foreign-keys><key app=”EN” db-id=”5ardrpxr60pvfnef52axpsxpptazw02s9pvw” timestamp=”1253599893″>4275</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Azam, N.</author><author>Zhang, M. Y.</author><author>Wang, X.</author><author>Tenenhouse, H. S.</author><author>Portale, A. A.</author></authors></contributors><titles><title>Disordered regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase gene expression by phosphorus in X-linked hypophosphatemic (hyp) mice</title><secondary-title>Endocrinology</secondary-title></titles><periodical><full-title>Endocrinology</full-title><abbr-1>Endocrinology</abbr-1></periodical><pages>3463-8</pages><volume>144</volume><number>8</number><dates><year>2003</year></dates><label>22747512</label><urls></urls></record></Cite></EndNote>(Azam et al. 2003). The disease is characterised by the excessive renal excretion of serum phosphate leading to hypophosphatemia. Hypophosphatemia is generally considered to result in reduced hydroxyapatite (bone mineral) formation resulting in under-mineralisation of the skeleton or rickets (Figure 1). XLH usually presents in late infancy as growth retardation, skeletal deformities and rickets become apparent. XLH children display a delay in walking, bowed legs, craniostenosis, dental abscesses, entesopathy, fractures, and bone pain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWtpdGllPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWtpdGllPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48
UmVjTnVtPjIyPC9SZWNOdW0+PERpc3BsYXlUZXh0PihMaW5nbGFydCBldCBhbC4gMjAxNDsgTWFr
aXRpZSBldCBhbC4gMjAwMyk8L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjI8L3Jl
Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ4ZndmeHM5djJ6cnBl
OWVyMmE5cHdkOWZ4djV6MnY5MndlNWQiIHRpbWVzdGFtcD0iMTUxOTc5NDI4NSI+MjI8L2tleT48
a2V5IGFwcD0iRU5XZWIiIGRiLWlkPSIiPjA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUg
bmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9y
cz48YXV0aG9yPk1ha2l0aWUsIE8uPC9hdXRob3I+PGF1dGhvcj5Eb3JpYSwgQS48L2F1dGhvcj48
YXV0aG9yPktvb2gsIFMuIFcuPC9hdXRob3I+PGF1dGhvcj5Db2xlLCBXLiBHLjwvYXV0aG9yPjxh
dXRob3I+RGFuZW1hbiwgQS48L2F1dGhvcj48YXV0aG9yPlNvY2hldHQsIEUuPC9hdXRob3I+PC9h
dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGl2aXNpb24gb2YgRW5kb2NyaW5v
bG9neSwgVGhlIEhvc3BpdGFsIGZvciBTaWNrIENoaWxkcmVuLCBVbml2ZXJzaXR5IG9mIFRvcm9u
dG8sIFRvcm9udG8sIE9udGFyaW8sIENhbmFkYSBNNUcgMVg4LiBvdXRpLm1ha2l0aWVAaGVsc2lu
a2kuZmk8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5FYXJseSB0cmVhdG1lbnQgaW1wcm92
ZXMgZ3Jvd3RoIGFuZCBiaW9jaGVtaWNhbCBhbmQgcmFkaW9ncmFwaGljIG91dGNvbWUgaW4gWC1s
aW5rZWQgaHlwb3Bob3NwaGF0ZW1pYyByaWNrZXRzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkog
Q2xpbiBFbmRvY3Jpbm9sIE1ldGFiPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj
YWw+PGZ1bGwtdGl0bGU+SiBDbGluIEVuZG9jcmlub2wgTWV0YWI8L2Z1bGwtdGl0bGU+PC9wZXJp
b2RpY2FsPjxwYWdlcz4zNTkxLTc8L3BhZ2VzPjx2b2x1bWU+ODg8L3ZvbHVtZT48bnVtYmVyPjg8
L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWdlIG9mIE9uc2V0PC9rZXl3b3JkPjxrZXl3b3Jk
PkJvZHkgSGVpZ2h0L2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5Cb25lIGFuZCBCb25l
cy9kaWFnbm9zdGljIGltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+Q2FsY2l0cmlvbC9ibG9vZDwv
a2V5d29yZD48a2V5d29yZD5DaGlsZDwva2V5d29yZD48a2V5d29yZD5DaGlsZCwgUHJlc2Nob29s
PC9rZXl3b3JkPjxrZXl3b3JkPkdyb3d0aC8qZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3Jk
Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5IeXBvcGhvc3BoYXRlbWlhL2Jsb29kPC9rZXl3b3Jk
PjxrZXl3b3JkPkh5cG9waG9zcGhhdGVtaWEsIEZhbWlsaWFsL2RpYWdub3N0aWMgaW1hZ2luZy9t
ZXRhYm9saXNtLyp0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkluZmFudDwva2V5d29yZD48a2V5
d29yZD5SYWRpb2dyYXBoeTwva2V5d29yZD48a2V5d29yZD5SZXRyb3NwZWN0aXZlIFN0dWRpZXM8
L2tleXdvcmQ+PGtleXdvcmQ+VHJlYXRtZW50IE91dGNvbWU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48
ZGF0ZXM+PHllYXI+MjAwMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkF1ZzwvZGF0ZT48L3B1Yi1k
YXRlcz48L2RhdGVzPjxpc2JuPjAwMjEtOTcyWCAoUHJpbnQpJiN4RDswMDIxLTk3MlggKExpbmtp
bmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjEyOTE1NjQxPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxy
ZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xMjkx
NTY0MTwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+
MTAuMTIxMC9qYy4yMDAzLTAzMDAzNjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+
PC9DaXRlPjxDaXRlPjxBdXRob3I+TGluZ2xhcnQ8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS
ZWNOdW0+ODk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjg5PC9yZWMtbnVtYmVyPjxmb3Jl
aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0ieGZ3ZnhzOXYyenJwZTllcjJhOXB3ZDlmeHY1
ejJ2OTJ3ZTVkIiB0aW1lc3RhbXA9IjE1MzM1Mjc5NTUiPjg5PC9rZXk+PGtleSBhcHA9IkVOV2Vi
IiBkYi1pZD0iIj4wPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwg
QXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5MaW5n
bGFydCwgQS48L2F1dGhvcj48YXV0aG9yPkJpb3NzZS1EdXBsYW4sIE0uPC9hdXRob3I+PGF1dGhv
cj5CcmlvdCwgSy48L2F1dGhvcj48YXV0aG9yPkNoYXVzc2FpbiwgQy48L2F1dGhvcj48YXV0aG9y
PkVzdGVybGUsIEwuPC9hdXRob3I+PGF1dGhvcj5HdWlsbGF1bWUtQ3ppdHJvbSwgUy48L2F1dGhv
cj48YXV0aG9yPkthbWVuaWNreSwgUC48L2F1dGhvcj48YXV0aG9yPk5ldm91eCwgSi48L2F1dGhv
cj48YXV0aG9yPlByaWUsIEQuPC9hdXRob3I+PGF1dGhvcj5Sb3RoZW5idWhsZXIsIEEuPC9hdXRo
b3I+PGF1dGhvcj5XaWNhcnQsIFAuPC9hdXRob3I+PGF1dGhvcj5IYXJ2ZW5ndCwgUC48L2F1dGhv
cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5TZXJ2aWNlIGQmYXBvcztF
bmRvY3Jpbm9sb2dpZSBldCBEaWFiZXRvbG9naWUgZGUgbCZhcG9zO0VuZmFudCBTZXJ2aWNlIGRl
IFBlZGlhdHJpZSBnZW5lcmFsZSAtIENvbnN1bHRhdGlvbiBkZSByaHVtYXRvbG9naWUgU2Vydmlj
ZSBkJmFwb3M7RW5kb2NyaW5vbG9naWUgZXQgZGVzIE1hbGFkaWVzIGRlIGxhIFJlcHJvZHVjdGlv
biBTZXJ2aWNlIGQmYXBvcztPUkwgZXQgY2hpcnVyZ2llIGNlcnZpY28tbWF4aWxsby1mYWNpYWxl
SG9waXRhbCBCaWNldHJlLCBBUEhQLCA3OCBydWUgZHUgR2VuZXJhbCBMZWNsZXJjLCA5NDI3MCBM
ZSBLcmVtbGluIEJpY2V0cmUsIEZyYW5jZSBVbml2ZXJzaXRlIFBhcmlzIDExRmFjdWx0ZSBkZSBN
ZWRlY2luZSwgSG9waXRhbCBCaWNldHJlLCA3MCBydWUgZHUgR2VuZXJhbCBMZWNsZXJjLCA5NDI3
MCBMZSBLcmVtbGluLUJpY2V0cmUsIEZyYW5jZSBDZW50cmUgZGUgUmVmZXJlbmNlIGRlcyBNYWxh
ZGllcyBSYXJlcyBkdSBNZXRhYm9saXNtZSBkdSBDYWxjaXVtIGV0IGR1IFBob3NwaG9yZUxlIEty
ZW1saW4tQmljZXRyZSwgRnJhbmNlIFNlcnZpY2UgZCZhcG9zO09kb250b2xvZ2llLU1hbGFkaWVz
IFJhcmVzIEhvcGl0YWwgQnJldG9ubmVhdSAyIHJ1ZSBDYXJwZWF1eDc1MDE4IFBhcmlzLCBGcmFu
Y2UgVW5pdmVyc2l0ZSBQYXJpcyBEZXNjYXJ0ZXMgMTIgUnVlIGRlIGwmYXBvcztFY29sZSBkZSBN
ZWRlY2luZTc1MDA2IFBhcmlzLCBGcmFuY2UgU2VydmljZSBSaHVtYXRvbG9naWUgQiBIb3BpdGFs
IENvY2hpbkFQSFAsIDI3LCBydWUgZHUgRmF1Ym91cmcgU2FpbnQtSmFjcXVlcywgNzUwMTQgUGFy
aXMsIEZyYW5jZSBDZW50cmUgZGUgUmVmZXJlbmNlIGRlcyBNYWxhZGllcyBSYXJlcyBkZXMgTWFs
YWRpZXMgQXV0by1JbmZsYW1tYXRvaXJlcyBSYXJlcyBkZSBsJmFwb3M7RW5mYW50TGUgS3JlbWxp
biBCaWNldHJlLCBGcmFuY2UgU2VydmljZSBkJmFwb3M7ZXhwbG9yYXRpb25zIGZvbmN0aW9ubmVs
bGVzIHJlbmFsZXMgU2VydmljZSBkZSBDaGlydXJnaWUgaW5mYW50aWxlIG9ydGhvcGVkaXF1ZUhv
cGl0YWwgTmVja2VyLUVuZmFudHMgTWFsYWRlcywgMTQ5IHJ1ZSBkZSBTZXZyZXMsIDc1MDE1IFBh
cmlzLCBGcmFuY2UgQXNzb2NpYXRpb24gZGUgcGF0aWVudHMgUlZSSC1YTEgyMCBydWUgTWVybGlu
IGRlIFRoaW9udmlsbGUsIDkyMTUwIFN1cmVzbmVzLCBGcmFuY2UuPC9hdXRoLWFkZHJlc3M+PHRp
dGxlcz48dGl0bGU+VGhlcmFwZXV0aWMgbWFuYWdlbWVudCBvZiBoeXBvcGhvc3BoYXRlbWljIHJp
Y2tldHMgZnJvbSBpbmZhbmN5IHRvIGFkdWx0aG9vZDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5F
bmRvY3IgQ29ubmVjdDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxs
LXRpdGxlPkVuZG9jciBDb25uZWN0PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+UjEz
LTMwPC9wYWdlcz48dm9sdW1lPjM8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4y
MDE0LzAyLzIwPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5YLWxpbmtlZCBoeXBvcGhvc3Bo
YXRlbWljIHJpY2tldHM8L2tleXdvcmQ+PGtleXdvcmQ+Ym9uZTwva2V5d29yZD48a2V5d29yZD5j
YWxjaXVtPC9rZXl3b3JkPjxrZXl3b3JkPnJhcmUgZGlzZWFzZXMvc3luZHJvbWVzPC9rZXl3b3Jk
Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PC9kYXRlcz48aXNibj4yMDQ5LTM2
MTQgKFByaW50KSYjeEQ7MjA0OS0zNjE0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4y
NDU1MDMyMjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93
d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjQ1NTAzMjI8L3VybD48L3JlbGF0ZWQtdXJscz48
L3VybHM+PGN1c3RvbTI+UE1DMzk1OTczMDwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1u
dW0+MTAuMTUzMC9FQy0xMy0wMTAzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48
L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE.DATA (Linglart et al. 2014; Makitie et al. 2003). The principal symptoms of XLH in adults are bone pain, joint pain, and stiffness. As patients age, long-term weight bearing on misaligned joints often results in osteoarthritis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Che et al. 2016). While treatment with oral phosphate and active vitamin D compounds, such as 1,25(OH)2D, are a common therapy for XLH, treatment from infancy results in the best outcomes for children suffering with XLH ADDIN EN.CITE <EndNote><Cite><Author>Makitie</Author><Year>2003</Year><RecNum>22</RecNum><DisplayText>(Makitie et al. 2003)</DisplayText><record><rec-number>22</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519794285″>22</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Makitie, O.</author><author>Doria, A.</author><author>Kooh, S. W.</author><author>Cole, W. G.</author><author>Daneman, A.</author><author>Sochett, E.</author></authors></contributors><auth-address>Division of Endocrinology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8. [email protected]</auth-address><titles><title>Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets</title><secondary-title>J Clin Endocrinol Metab</secondary-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><pages>3591-7</pages><volume>88</volume><number>8</number><keywords><keyword>Age of Onset</keyword><keyword>Body Height/drug effects</keyword><keyword>Bone and Bones/diagnostic imaging</keyword><keyword>Calcitriol/blood</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Growth/*drug effects</keyword><keyword>Humans</keyword><keyword>Hypophosphatemia/blood</keyword><keyword>Hypophosphatemia, Familial/diagnostic imaging/metabolism/*therapy</keyword><keyword>Infant</keyword><keyword>Radiography</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2003</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0021-972X (Print) 0021-972X (Linking)</isbn><accession-num>12915641</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/12915641</url></related-urls></urls><electronic-resource-num>10.1210/jc.2003-030036</electronic-resource-num></record></Cite></EndNote>(Makitie et al. 2003). However, treatment of XLH patients frequently results either in severe side effects such as hypercalcaemia, or has no positive effects on bone health ADDIN EN.CITE <EndNote><Cite><Author>Makitie</Author><Year>2003</Year><RecNum>22</RecNum><DisplayText>(Makitie et al. 2003)</DisplayText><record><rec-number>22</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519794285″>22</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Makitie, O.</author><author>Doria, A.</author><author>Kooh, S. W.</author><author>Cole, W. G.</author><author>Daneman, A.</author><author>Sochett, E.</author></authors></contributors><auth-address>Division of Endocrinology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8. [email protected]</auth-address><titles><title>Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets</title><secondary-title>J Clin Endocrinol Metab</secondary-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><pages>3591-7</pages><volume>88</volume><number>8</number><keywords><keyword>Age of Onset</keyword><keyword>Body Height/drug effects</keyword><keyword>Bone and Bones/diagnostic imaging</keyword><keyword>Calcitriol/blood</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Growth/*drug effects</keyword><keyword>Humans</keyword><keyword>Hypophosphatemia/blood</keyword><keyword>Hypophosphatemia, Familial/diagnostic imaging/metabolism/*therapy</keyword><keyword>Infant</keyword><keyword>Radiography</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2003</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0021-972X (Print) 0021-972X (Linking)</isbn><accession-num>12915641</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/12915641</url></related-urls></urls><electronic-resource-num>10.1210/jc.2003-030036</electronic-resource-num></record></Cite></EndNote>(Makitie et al. 2003). While recent developments have provided new therapeutic options, numerous side effects have been reported ADDIN EN.CITE <EndNote><Cite><Author>Carpenter</Author><Year>2011</Year><RecNum>98</RecNum><DisplayText>(Carpenter et al. 2011)</DisplayText><record><rec-number>98</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1536560091″>98</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Carpenter, T. O.</author><author>Imel, E. A.</author><author>Holm, I. A.</author><author>Jan de Beur, S. M.</author><author>Insogna, K. L.</author></authors></contributors><auth-address>Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520-8064, USA. [email protected]</auth-address><titles><title>A clinician&apos;s guide to X-linked hypophosphatemia</title><secondary-title>J Bone Miner Res</secondary-title></titles><periodical><full-title>J Bone Miner Res</full-title></periodical><pages>1381-8</pages><volume>26</volume><number>7</number><edition>2011/05/04</edition><keywords><keyword>*Familial Hypophosphatemic Rickets/diagnostic</keyword><keyword>imaging/pathology/physiopathology/therapy</keyword><keyword>*Genetic Diseases, X-Linked</keyword><keyword>Humans</keyword><keyword>Practice Guidelines as Topic</keyword><keyword>Radiography</keyword></keywords><dates><year>2011</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1523-4681 (Electronic) 0884-0431 (Linking)</isbn><accession-num>21538511</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/21538511</url></related-urls></urls><custom2>PMC3157040</custom2><electronic-resource-num>10.1002/jbmr.340</electronic-resource-num></record></Cite></EndNote>(Carpenter et al. 2011). Thus, further efforts are required to establish effective therapies which heal the under-mineralised bone disorder without causing significant side effects.
25761952510790Figure 2: XLH Pathophysiology00Figure 2: XLH PathophysiologyThe cause of XLH: In XLH, a loss-of-function mutation in the phosphate-regulating endopeptidase homolog, X-linked (PHEX) gene results in excessive levels of the Fibroblast Growth Factor 23 (FGF23) protein PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWlmaGVpdC1OZXN0bGVyPC9BdXRob3I+PFllYXI+MjAx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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWlmaGVpdC1OZXN0bGVyPC9BdXRob3I+PFllYXI+MjAx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ADDIN EN.CITE.DATA (Leifheit-Nestler et al. 2017). Fibroblast Growth Factor 23 (FGF23) is a bone derived hormone that was relatively recently discovered in 2000. FGF23 is mainly produced in two bone cell types, osteoblasts and osteocytes, and is normally produced in response to high levels of circulating phosphorus and active vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D) ADDIN EN.CITE <EndNote><Cite><Author>Erben</Author><Year>2017</Year><RecNum>8</RecNum><DisplayText>(Erben 2017)</DisplayText><record><rec-number>8</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519791986″>8</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Erben, R. G.</author></authors></contributors><auth-address>1 Department of Biomedical Sciences, Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, Vienna, Austria.</auth-address><titles><title>Pleiotropic Actions of FGF23</title><secondary-title>Toxicol Pathol</secondary-title></titles><periodical><full-title>Toxicol Pathol</full-title></periodical><pages>904-910</pages><volume>45</volume><number>7</number><keywords><keyword>bone</keyword><keyword>bone mineralization</keyword><keyword>cardiovascular system</keyword><keyword>endocrine system</keyword><keyword>mineral metabolism</keyword><keyword>renal</keyword><keyword>transgenic animals</keyword></keywords><dates><year>2017</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1533-1601 (Electronic) 0192-6233 (Linking)</isbn><accession-num>29096595</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/29096595</url></related-urls></urls><electronic-resource-num>10.1177/0192623317737469</electronic-resource-num></record></Cite></EndNote>(Erben 2017). In a feedback mechanism, FGF23 is responsible for the promoting the excretion of phosphorus as well as reducing 1,25(OH)2D levels (Figure 2) ADDIN EN.CITE <EndNote><Cite><Author>Portale</Author><Year>2012</Year><RecNum>66</RecNum><DisplayText>(Portale, Perwad &amp; Miller 2012)</DisplayText><record><rec-number>66</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533032235″>66</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Book Section”>5</ref-type><contributors><authors><author>Portale, Anthony A.</author><author>Perwad, Farzana</author><author>Miller, Walter L.</author></authors></contributors><titles><title>Rickets Due to Hereditary Abnormalities of Vitamin D Synthesis or Action</title><secondary-title>Pediatric Bone</secondary-title></titles><pages>679-698</pages><dates><year>2012</year></dates><isbn>9780123820402</isbn><urls></urls><electronic-resource-num>10.1016/b978-0-12-382040-2.10025-5</electronic-resource-num></record></Cite></EndNote>(Portale, Perwad & Miller 2012). . In XLH, elevated FGF23 levels prevent the renal proximal tubular phosphate reabsorption, by reducing Sodium-Phosphate transporters (NaPi2a and NaPi2c) as well as inhibits the intestinal sodium-phosphate transporter (NaPi2b), resulting in inappropriately high phosphate wasting PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (Kido et al. 2013). Excess FGF23 levels also acts to markedly reduce 1,25(OH)2D levels both by supressing the hydroxylase 25-hydroxyvitamin D 1?-hydroxylase enzyme, CYP27B1, which is responsible for the conversion of inactive vitamin D (25(OH)D) to 1,25(OH)2D, and by inducing the 25-hydroxyvitamin D 24-hydroxylase enzymevitamin D catabolizing enzyme, CYP24A1, which acts to both convertt 1,25(OH)2D, and as well as 25(OH)D, to inactive metabolites PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Liu et al. 2016a).

We Will Write a Custom Essay Specifically
For You For Only $13.90/page!


order now

In addition to XLH, several other disorders in the regulation of FGF23 result in hypophosphatemia and hypovitaminosis D with similar effects on poor bone mineralisation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PaGF0YTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PaGF0YTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl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 EN.CITE.DATA (Ohata et al. 2014). Converse to effects of FGF23 excess disorders, if FGF23 is ablated, hyperphosphatemia and hypophosphaturia result PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaXRhcmE8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaXRhcmE8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS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=
ADDIN EN.CITE.DATA (Sitara et al. 2006). The role of phosphate in XLH: Phosphate, whilst less tightly regulated than calcium, plays a critical role in bone homeostasis including directly contributing to chondrocyte maturation and skeletal mineralisation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LbzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LbzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051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ADDIN EN.CITE.DATA (Ko et al. 2016). The main regulator of serum pPhosphate levels isis easily effected by levels of FGF23. However, , Parathyroid Hormone (PTH), and active vitamin D (1,25(OH)2D3 contribute to the regulating of phosphate levels as well). As discussed, in XLH, elevated FGF23 levels prevent the renal proximal tubular phosphate reabsorption, by reducing Sodium-Phosphate transporters (NaPi2a and NaPi2c) as well as inhibits the intestinal sodium-phosphate transporter (NaPi2b). When supplemented with phosphate alone, XLH patients show a partial improvement in the rachitic phenotype, but no improvement in endosteal bone mineralisation ADDIN EN.CITE <EndNote><Cite><Author>Marie</Author><Year>1981</Year><RecNum>17</RecNum><DisplayText>(Marie, Travers &amp; Glorieux 1981)</DisplayText><record><rec-number>17</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519793688″>17</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P. J.</author><author>Travers, R.</author><author>Glorieux, F. H.</author></authors></contributors><titles><title>Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse</title><secondary-title>Journal of Clinical Investigation</secondary-title></titles><periodical><full-title>Journal of Clinical Investigation</full-title></periodical><pages>911-914</pages><volume>67</volume><number>3</number><dates><year>1981</year></dates><isbn>0021-9738</isbn><urls></urls><electronic-resource-num>10.1172/jci110110</electronic-resource-num></record></Cite></EndNote>(Marie, Travers & Glorieux 1981). This effect of phosphate is considered to directly effect of chondrocyte differentiation and apoptosis…….(REFs). Consistent with the effect of phosphate on the growth plate, pPhosphate supplementation also only works in the children where the activity of growth plate is significant young. N, with no benefits of phosphate were observed seen inin adult patients with osteomalacia (the adult form of rickets) ADDIN EN.CITE <EndNote><Cite><Author>Marie</Author><Year>1981</Year><RecNum>17</RecNum><DisplayText>(Marie, Travers &amp; Glorieux 1981)</DisplayText><record><rec-number>17</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519793688″>17</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P. J.</author><author>Travers, R.</author><author>Glorieux, F. H.</author></authors></contributors><titles><title>Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse</title><secondary-title>Journal of Clinical Investigation</secondary-title></titles><periodical><full-title>Journal of Clinical Investigation</full-title></periodical><pages>911-914</pages><volume>67</volume><number>3</number><dates><year>1981</year></dates><isbn>0021-9738</isbn><urls></urls><electronic-resource-num>10.1172/jci110110</electronic-resource-num></record></Cite></EndNote>(Marie, Travers & Glorieux 1981). 3364302110478Figure 3: The mechanism of coordinated bone mineralisation in osteocytes.Figure 3: The mechanism of coordinated bone mineralisation in osteocytes.Phosphate plays a critical role in the mineralisation of the skeleton. The formation of hydroxyapatite (HAP) in the skeleton requires combination of inorganic Phosphate (Pi) with calcium (Ca) (Figure 3). The presentation of inorganic phosphate for combination with calcium is not dependent on serum phosphate levels, but rather by the co-ordinated production by osteoblasts. This process is governed by at least three cell membrane associated proteins Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (NPP1), 3376295435610Figure 3: The mechanism of coordinated bone mineralisation in osteocytes.Figure 3: The mechanism of coordinated bone mineralisation in osteocytes.Progressive Ankylosis Protein (ANK) and Tissue Non-specific Alkaline Phosphatase (TNAP). Conversion of pyrophosphate (PPi) to Pi by TNAP is common to mineralising osteoblasts. A high PPi to Pi ratio has been shown to be inhibitory for HAP formation. In the mouse model of XLH (Hyp mice), excessive FGF23 contributes to PPi accumulation, by reducing TNAP expression and decreasing the conversion to Pi (REF). These data partly explain why elevating serum phosphate levels does not contribute to improving bone minersalisation in XLH. Furthermore, the key to improving bone mineralsition in XLH may lie in reducing PPi:Pi ratio through regulation of one or more osteoblastic genes in the bone mineralisation pathway. 336359512700Figure 4: Basic principles of vitamin D synthesis and catabolism.Figure 4: Basic principles of vitamin D synthesis and catabolism.In healthy patients, hypophosphatemia stimulates the synthesis of 1,25(OH)D3, and hyperphosphatemia down regulates the synthesis of 1,25(OH)D3 ADDIN EN.CITE <EndNote><Cite><Author>Portale</Author><Year>2012</Year><RecNum>66</RecNum><DisplayText>(Portale, Perwad &amp; Miller 2012)</DisplayText><record><rec-number>66</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533032235″>66</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Book Section”>5</ref-type><contributors><authors><author>Portale, Anthony A.</author><author>Perwad, Farzana</author><author>Miller, Walter L.</author></authors></contributors><titles><title>Rickets Due to Hereditary Abnormalities of Vitamin D Synthesis or Action</title><secondary-title>Pediatric Bone</secondary-title></titles><pages>679-698</pages><dates><year>2012</year></dates><isbn>9780123820402</isbn><urls></urls><electronic-resource-num>10.1016/b978-0-12-382040-2.10025-5</electronic-resource-num></record></Cite></EndNote>(Portale, Perwad & Miller 2012). In XLH patients, hypophosphatemia results in a drop in 1,25(OH)D3, not an increase ADDIN EN.CITE <EndNote><Cite><Author>Portale</Author><Year>2012</Year><RecNum>66</RecNum><DisplayText>(Portale, Perwad &amp; Miller 2012)</DisplayText><record><rec-number>66</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533032235″>66</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Book Section”>5</ref-type><contributors><authors><author>Portale, Anthony A.</author><author>Perwad, Farzana</author><author>Miller, Walter L.</author></authors></contributors><titles><title>Rickets Due to Hereditary Abnormalities of Vitamin D Synthesis or Action</title><secondary-title>Pediatric Bone</secondary-title></titles><pages>679-698</pages><dates><year>2012</year></dates><isbn>9780123820402</isbn><urls></urls><electronic-resource-num>10.1016/b978-0-12-382040-2.10025-5</electronic-resource-num></record></Cite></EndNote>(Portale, Perwad & Miller 2012). To make matters worse, CYP24A1 levels increase and therefore a high rate of catabolism ensues ADDIN EN.CITE <EndNote><Cite><Author>Portale</Author><Year>2012</Year><RecNum>66</RecNum><DisplayText>(Portale, Perwad &amp; Miller 2012)</DisplayText><record><rec-number>66</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533032235″>66</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Book Section”>5</ref-type><contributors><authors><author>Portale, Anthony A.</author><author>Perwad, Farzana</author><author>Miller, Walter L.</author></authors></contributors><titles><title>Rickets Due to Hereditary Abnormalities of Vitamin D Synthesis or Action</title><secondary-title>Pediatric Bone</secondary-title></titles><pages>679-698</pages><dates><year>2012</year></dates><isbn>9780123820402</isbn><urls></urls><electronic-resource-num>10.1016/b978-0-12-382040-2.10025-5</electronic-resource-num></record></Cite></EndNote>(Portale, Perwad & Miller 2012). Less vitamin D in, and increased vitamin D catabolised, results in reduced bone mineral levels. Some speculation around why this happens was published in 1980. Meyer et al. suggested that the low phosphate levels trigger an increase in serum calcium levels, and therefore a reduction in PTH levels. The drop in PTH may explain the low 1,25(OH)D3 levels. When supplemented with phosphate alone, XLH patients show a partial improvement in the rachitic phenotype, but no improvement in endosteal bone mineralisation ADDIN EN.CITE <EndNote><Cite><Author>Marie</Author><Year>1981</Year><RecNum>17</RecNum><DisplayText>(Marie, Travers &amp; Glorieux 1981)</DisplayText><record><rec-number>17</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519793688″>17</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P. J.</author><author>Travers, R.</author><author>Glorieux, F. H.</author></authors></contributors><titles><title>Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse</title><secondary-title>Journal of Clinical Investigation</secondary-title></titles><periodical><full-title>Journal of Clinical Investigation</full-title></periodical><pages>911-914</pages><volume>67</volume><number>3</number><dates><year>1981</year></dates><isbn>0021-9738</isbn><urls></urls><electronic-resource-num>10.1172/jci110110</electronic-resource-num></record></Cite></EndNote>(Marie, Travers & Glorieux 1981). Phosphate supplementation also only works in the young, with no benefits seen in patients with osteomalacia (the adult form of rickets) ADDIN EN.CITE <EndNote><Cite><Author>Marie</Author><Year>1981</Year><RecNum>17</RecNum><DisplayText>(Marie, Travers &amp; Glorieux 1981)</DisplayText><record><rec-number>17</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519793688″>17</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P. J.</author><author>Travers, R.</author><author>Glorieux, F. H.</author></authors></contributors><titles><title>Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse</title><secondary-title>Journal of Clinical Investigation</secondary-title></titles><periodical><full-title>Journal of Clinical Investigation</full-title></periodical><pages>911-914</pages><volume>67</volume><number>3</number><dates><year>1981</year></dates><isbn>0021-9738</isbn><urls></urls><electronic-resource-num>10.1172/jci110110</electronic-resource-num></record></Cite></EndNote>(Marie, Travers & Glorieux 1981). Role of Vitamin D therapy and in XLH: The vitamin D endocrine system is responsible for the maintenance of calcium homoeostasis and skeletal growth ADDIN EN.CITE <EndNote><Cite><Author>Rowling</Author><Year>2007</Year><RecNum>81</RecNum><DisplayText>(Rowling, Matthew J et al. 2007)</DisplayText><record><rec-number>81</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533113728″>81</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Rowling, Matthew J</author><author>Gliniak, Christy</author><author>Welsh, JoEllen</author><author>Fleet, James C</author></authors></contributors><titles><title>High dietary vitamin D prevents hypocalcemia and osteomalacia in CYP27B1 knockout mice</title><secondary-title>The Journal of nutrition</secondary-title></titles><periodical><full-title>The Journal of nutrition</full-title></periodical><pages>2608-2615</pages><volume>137</volume><number>12</number><dates><year>2007</year></dates><isbn>0022-3166</isbn><urls><related-urls><url>https://watermark.silverchair.com/2608.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAcAwggG8BgkqhkiG9w0BBwagggGtMIIBqQIBADCCAaIGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMpmD_KmwRd4sGvFgjAgEQgIIBc6dnUxoCZL1YaBZdkc2ucI5X1-RQfXvPZWKQ02OVcRZZvOFjl1Fz9SCa38bb7d0d5Vcljd1q1Vk8la1MlnM7PMUNOyzIRx45OQEB8TooskRO12tczIL0gsaABrtQppQkj0WZQua03_RzIAmUbsDWE_cdlbotQBj7iAISYqr0c1s7JT8xPz7I3tRf6i2QNLpI106GHBW_VJGveUsgo1UDr3ZvlVx0esTI587hPzZaRYsGaYI6NPZI5RqgjQoCMaIaIOfLdD2wB7r094DMgSOrQLtaGD3HUoBbsaJBgOX_Uq7WA3m4leOAGp2gsvWHh8zXyWH4bzJZP6Rcb_Y1m4T4pRO_jRrFNDOngvpP-REW63Mx55_cj3vzDYXc8J7Erzi-NMh47kE2n53mnes4hDMin3TpPqg0LV9f958aKTvcVHdD1ih-kicgSYa12aDVlKfjb3hpP90p13eZfJh3dvEDS8OmEgBaLHu9TbopBiELK2nrEm-4</url></related-urls></urls></record></Cite></EndNote>(Rowling, Matthew J et al. 2007). Optimal bone health is achieved when adequate vitamin vitamin D is metabolised and mediated properly through genes in the intestine, kidney, and bone ADDIN EN.CITE <EndNote><Cite><Author>Rowling</Author><Year>2007</Year><RecNum>81</RecNum><DisplayText>(Rowling, Matthew J et al. 2007)</DisplayText><record><rec-number>81</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533113728″>81</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Rowling, Matthew J</author><author>Gliniak, Christy</author><author>Welsh, JoEllen</author><author>Fleet, James C</author></authors></contributors><titles><title>High dietary vitamin D prevents hypocalcemia and osteomalacia in CYP27B1 knockout mice</title><secondary-title>The Journal of nutrition</secondary-title></titles><periodical><full-title>The Journal of nutrition</full-title></periodical><pages>2608-2615</pages><volume>137</volume><number>12</number><dates><year>2007</year></dates><isbn>0022-3166</isbn><urls><related-urls><url>https://watermark.silverchair.com/2608.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAcAwggG8BgkqhkiG9w0BBwagggGtMIIBqQIBADCCAaIGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMpmD_KmwRd4sGvFgjAgEQgIIBc6dnUxoCZL1YaBZdkc2ucI5X1-RQfXvPZWKQ02OVcRZZvOFjl1Fz9SCa38bb7d0d5Vcljd1q1Vk8la1MlnM7PMUNOyzIRx45OQEB8TooskRO12tczIL0gsaABrtQppQkj0WZQua03_RzIAmUbsDWE_cdlbotQBj7iAISYqr0c1s7JT8xPz7I3tRf6i2QNLpI106GHBW_VJGveUsgo1UDr3ZvlVx0esTI587hPzZaRYsGaYI6NPZI5RqgjQoCMaIaIOfLdD2wB7r094DMgSOrQLtaGD3HUoBbsaJBgOX_Uq7WA3m4leOAGp2gsvWHh8zXyWH4bzJZP6Rcb_Y1m4T4pRO_jRrFNDOngvpP-REW63Mx55_cj3vzDYXc8J7Erzi-NMh47kE2n53mnes4hDMin3TpPqg0LV9f958aKTvcVHdD1ih-kicgSYa12aDVlKfjb3hpP90p13eZfJh3dvEDS8OmEgBaLHu9TbopBiELK2nrEm-4</url></related-urls></urls></record></Cite></EndNote>(Rowling, Matthew J et al. 2007). While vVitamin D can be obtained through diet and supplements, the predominant source for vitamin D is via or through the skin upon exposure to U V radiation from the sun. These forms of vitamin D are parent calciferols D2 and D3. Metabolism of these calciferolsVitamin D3, formed in the skin, is metabolised further occurs in the liver to form 25-hydroxyvitamin D (25(OH)D), mediated primarily by the hepatic enzymes CYP2R1 and CYP27A1 (Figure 4) (REF). 25(OH)D is the major circulating metabolite of vitamin D and while it is itself This new form of vitamin is 25(OH)D3. It has low affinity for the vitamin D receptor (unlikely to compete with active vitamin D), and is considered inactive, . the circulating levels of 25(OH)D is used clinically to determine a person’s vitamin D status (REF). For vitamin D to exert its activity, 25(OH)D3 is required to be further metabolised to 1,25(OH)2D catalysed by the renal cytochrome enzyme CYP27B1 enzymewhere hydroxylation results in calcitriol (active vitamin D). Active vitamin D, 1,25(OH)2D3, iOnce synthesised, active vitamin D can acts upon many tissues several via the binding the vitamin D receptor (VDR) and modulates various systems tissues PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3dsaW5nPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3dsaW5nPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48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ADDIN EN.CITE.DATA (Roizen et al. 2018; Rowling, Matthew J et al. 2007). While the classical action of 1,25(OH)2D is to stimulate intestinal calcium absorption, 1,25(OH)2D also and systems including thehas been shown to regulate the serval other systems including cardiovascular health, immune system, lung health, anti-neoplastic action in several red blood cells, cancers cells, skin maturation as well multiple direct roles in bone homeostasis (as reviewed in the parathyroid gland, gut, and bone. REF).s a ligand with high affinity for the vitamin D receptor PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3dsaW5nPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3dsaW5nPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48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ADDIN EN.CITE.DATA (Roizen et al. 2018; Rowling, Matthew J et al. 2007). Once synthesised, active vitamin D can act upon several tissues and systems including the immune system, red blood cells, cancer cells, the parathyroid gland, gut, and bone. Aside from bone diseases, inadequate vitamin D activity is associated with several other serious conditions such as chronic kidney disease (CKD), cancer, hepatic disease, cardiovascular disease, autoimmune disease, depression, and obesity ADDIN EN.CITE ;EndNote;;Cite;;Author;Rowling;/Author;;Year;2007;/Year;;RecNum;81;/RecNum;;DisplayText;(Rowling, Matthew J et al. 2007);/DisplayText;;record;;rec-number;81;/rec-number;;foreign-keys;;key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533113728″;81;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Rowling, Matthew J;/author;;author;Gliniak, Christy;/author;;author;Welsh, JoEllen;/author;;author;Fleet, James C;/author;;/authors;;/contributors;;titles;;title;High dietary vitamin D prevents hypocalcemia and osteomalacia in CYP27B1 knockout mice;/title;;secondary-title;The Journal of nutrition;/secondary-title;;/titles;;periodical;;full-title;The Journal of nutrition;/full-title;;/periodical;;pages;2608-2615;/pages;;volume;137;/volume;;number;12;/number;;dates;;year;2007;/year;;/dates;;isbn;0022-3166;/isbn;;urls;;related-urls;;url;https://watermark.silverchair.com/2608.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAcAwggG8BgkqhkiG9w0BBwagggGtMIIBqQIBADCCAaIGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMpmD_KmwRd4sGvFgjAgEQgIIBc6dnUxoCZL1YaBZdkc2ucI5X1-RQfXvPZWKQ02OVcRZZvOFjl1Fz9SCa38bb7d0d5Vcljd1q1Vk8la1MlnM7PMUNOyzIRx45OQEB8TooskRO12tczIL0gsaABrtQppQkj0WZQua03_RzIAmUbsDWE_cdlbotQBj7iAISYqr0c1s7JT8xPz7I3tRf6i2QNLpI106GHBW_VJGveUsgo1UDr3ZvlVx0esTI587hPzZaRYsGaYI6NPZI5RqgjQoCMaIaIOfLdD2wB7r094DMgSOrQLtaGD3HUoBbsaJBgOX_Uq7WA3m4leOAGp2gsvWHh8zXyWH4bzJZP6Rcb_Y1m4T4pRO_jRrFNDOngvpP-REW63Mx55_cj3vzDYXc8J7Erzi-NMh47kE2n53mnes4hDMin3TpPqg0LV9f958aKTvcVHdD1ih-kicgSYa12aDVlKfjb3hpP90p13eZfJh3dvEDS8OmEgBaLHu9TbopBiELK2nrEm-4;/url;;/related-urls;;/urls;;/record;;/Cite;;/EndNote;(Rowling, Matthew J et al. 2007). Nutritional vitamin D deficiency can be easily restored in the form of dietary modification, vitamin D analogues, or over the counter vitamin D metabolites. In vitamin D resistant rickets (VDRR), or XLH, excessive FGF23 actions results in lower renal 1,25(OH)D production. However, few studies have investigated the vitamin D status, as measured by 25(OH)D levels, in XLH patients. are often reported as only being slightly vitamin D deficient or even “vitamin D replete”, which, if they had normal phosphorus levels, would be correct. However, given the level of hypophosphatemia, one would expect the 1,25(OH)D3 to be far higher ADDIN EN.CITE ;EndNote;;Cite;;Author;Azam;/Author;;Year;2003;/Year;;RecNum;4275;/RecNum;;DisplayText;(Azam et al. 2003);/DisplayText;;record;;rec-number;4275;/rec-number;;foreign-keys;;key app=”EN” db-id=”5ardrpxr60pvfnef52axpsxpptazw02s9pvw” timestamp=”1253599893″;4275;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Azam, N.;/author;;author;Zhang, M. Y.;/author;;author;Wang, X.;/author;;author;Tenenhouse, H. S.;/author;;author;Portale, A. A.;/author;;/authors;;/contributors;;titles;;title;Disordered regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase gene expression by phosphorus in X-linked hypophosphatemic (hyp) mice;/title;;secondary-title;Endocrinology;/secondary-title;;/titles;;periodical;;full-title;Endocrinology;/full-title;;abbr-1;Endocrinology;/abbr-1;;/periodical;;pages;3463-8;/pages;;volume;144;/volume;;number;8;/number;;dates;;year;2003;/year;;/dates;;label;22747512;/label;;urls;;/urls;;/record;;/Cite;;/EndNote;(Azam et al. 2003). This gap in the knowledge is not unexpected given the XLH disease is considered to be disorder that impacts in renal activation of 1,25(OH)D, and not 25(OH)D production. Thus the focus of current therapies include administering 1,25(OH)2D3 to restore levels or to use a synthetic vitamin D analogues to mimics 1,25(OH)2D3 activity ADDIN EN.CITE ;EndNote;;Cite;;Author;Makitie;/Author;;Year;2003;/Year;;RecNum;22;/RecNum;;DisplayText;(Makitie et al. 2003);/DisplayText;;record;;rec-number;22;/rec-number;;foreign-keys;;key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519794285″;22;/key;;key app=”ENWeb” db-id=””;0;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Makitie, O.;/author;;author;Doria, A.;/author;;author;Kooh, S. W.;/author;;author;Cole, W. G.;/author;;author;Daneman, A.;/author;;author;Sochett, E.;/author;;/authors;;/contributors;;auth-address;Division of Endocrinology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8. [email protected];/auth-address;;titles;;title;Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets;/title;;secondary-title;J Clin Endocrinol Metab;/secondary-title;;/titles;;periodical;;full-title;J Clin Endocrinol Metab;/full-title;;/periodical;;pages;3591-7;/pages;;volume;88;/volume;;number;8;/number;;keywords;;keyword;Age of Onset;/keyword;;keyword;Body Height/drug effects;/keyword;;keyword;Bone and Bones/diagnostic imaging;/keyword;;keyword;Calcitriol/blood;/keyword;;keyword;Child;/keyword;;keyword;Child, Preschool;/keyword;;keyword;Growth/*drug effects</keyword><keyword>Humans</keyword><keyword>Hypophosphatemia/blood</keyword><keyword>Hypophosphatemia, Familial/diagnostic imaging/metabolism/*therapy</keyword><keyword>Infant</keyword><keyword>Radiography</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2003</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0021-972X (Print) 0021-972X (Linking)</isbn><accession-num>12915641</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/12915641</url></related-urls></urls><electronic-resource-num>10.1210/jc.2003-030036</electronic-resource-num></record></Cite></EndNote>(Makitie et al. 2003). Treatment is often supplied with oral phosphate which can be effective in improving growth, healing, and biochemical parameters in children. However, many children fail to respond to treatment for reasons that are not clear ADDIN EN.CITE <EndNote><Cite><Author>Makitie</Author><Year>2003</Year><RecNum>22</RecNum><DisplayText>(Makitie et al. 2003)</DisplayText><record><rec-number>22</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519794285″>22</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Makitie, O.</author><author>Doria, A.</author><author>Kooh, S. W.</author><author>Cole, W. G.</author><author>Daneman, A.</author><author>Sochett, E.</author></authors></contributors><auth-address>Division of Endocrinology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8. [email protected]</auth-address><titles><title>Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets</title><secondary-title>J Clin Endocrinol Metab</secondary-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><pages>3591-7</pages><volume>88</volume><number>8</number><keywords><keyword>Age of Onset</keyword><keyword>Body Height/drug effects</keyword><keyword>Bone and Bones/diagnostic imaging</keyword><keyword>Calcitriol/blood</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Growth/*drug effects</keyword><keyword>Humans</keyword><keyword>Hypophosphatemia/blood</keyword><keyword>Hypophosphatemia, Familial/diagnostic imaging/metabolism/*therapy</keyword><keyword>Infant</keyword><keyword>Radiography</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2003</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0021-972X (Print) 0021-972X (Linking)</isbn><accession-num>12915641</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/12915641</url></related-urls></urls><electronic-resource-num>10.1210/jc.2003-030036</electronic-resource-num></record></Cite></EndNote>(Makitie et al. 2003) and the concentration of vitamin D required to improve bone outcomes is far greater than usual and can lead to significant side effects. XLH patients are often reported as only being slightly vitamin D deficient or even “vitamin D replete”, which, if they had normal phosphorus levels, would be correct. However, given the level of hypophosphatemia, one would expect the 1,25(OH)D3 to be far higher ADDIN EN.CITE <EndNote><Cite><Author>Azam</Author><Year>2003</Year><RecNum>4275</RecNum><DisplayText>(Azam et al. 2003)</DisplayText><record><rec-number>4275</rec-number><foreign-keys><key app=”EN” db-id=”5ardrpxr60pvfnef52axpsxpptazw02s9pvw” timestamp=”1253599893″>4275</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Azam, N.</author><author>Zhang, M. Y.</author><author>Wang, X.</author><author>Tenenhouse, H. S.</author><author>Portale, A. A.</author></authors></contributors><titles><title>Disordered regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase gene expression by phosphorus in X-linked hypophosphatemic (hyp) mice</title><secondary-title>Endocrinology</secondary-title></titles><periodical><full-title>Endocrinology</full-title><abbr-1>Endocrinology</abbr-1></periodical><pages>3463-8</pages><volume>144</volume><number>8</number><dates><year>2003</year></dates><label>22747512</label><urls></urls></record></Cite></EndNote>(Azam et al. 2003). Current Therapies in XLH: In clinical settings, the normalisation of serum alkaline phosphatase levels and a radiological confirmation of healing rickets is the usual endpoint of treatment for children PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW5nbGFydDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW5nbGFydDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE.DATA (Linglart et al. 2014). Current therapies include active vitamin D (1,25(OH)D3), synthetic vitamin D analogues, phosphate, growth hormones, and surgery ADDIN EN.CITE <EndNote><Cite><Author>Makitie</Author><Year>2003</Year><RecNum>22</RecNum><DisplayText>(Makitie et al. 2003)</DisplayText><record><rec-number>22</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519794285″>22</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Makitie, O.</author><author>Doria, A.</author><author>Kooh, S. W.</author><author>Cole, W. G.</author><author>Daneman, A.</author><author>Sochett, E.</author></authors></contributors><auth-address>Division of Endocrinology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8. [email protected]</auth-address><titles><title>Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets</title><secondary-title>J Clin Endocrinol Metab</secondary-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><pages>3591-7</pages><volume>88</volume><number>8</number><keywords><keyword>Age of Onset</keyword><keyword>Body Height/drug effects</keyword><keyword>Bone and Bones/diagnostic imaging</keyword><keyword>Calcitriol/blood</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Growth/*drug effects</keyword><keyword>Humans</keyword><keyword>Hypophosphatemia/blood</keyword><keyword>Hypophosphatemia, Familial/diagnostic imaging/metabolism/*therapy</keyword><keyword>Infant</keyword><keyword>Radiography</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2003</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0021-972X (Print) 0021-972X (Linking)</isbn><accession-num>12915641</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/12915641</url></related-urls></urls><electronic-resource-num>10.1210/jc.2003-030036</electronic-resource-num></record></Cite></EndNote>(Makitie et al. 2003). Treatment with 1,25(OH)D3, or comparable analogue, in addition to phosphate has been shown to improve growth, healing, and biochemistry in children. Some children however fail to respond ADDIN EN.CITE <EndNote><Cite><Author>Makitie</Author><Year>2003</Year><RecNum>22</RecNum><DisplayText>(Makitie et al. 2003)</DisplayText><record><rec-number>22</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519794285″>22</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Makitie, O.</author><author>Doria, A.</author><author>Kooh, S. W.</author><author>Cole, W. G.</author><author>Daneman, A.</author><author>Sochett, E.</author></authors></contributors><auth-address>Division of Endocrinology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8. [email protected]</auth-address><titles><title>Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets</title><secondary-title>J Clin Endocrinol Metab</secondary-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><pages>3591-7</pages><volume>88</volume><number>8</number><keywords><keyword>Age of Onset</keyword><keyword>Body Height/drug effects</keyword><keyword>Bone and Bones/diagnostic imaging</keyword><keyword>Calcitriol/blood</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Growth/*drug effects</keyword><keyword>Humans</keyword><keyword>Hypophosphatemia/blood</keyword><keyword>Hypophosphatemia, Familial/diagnostic imaging/metabolism/*therapy</keyword><keyword>Infant</keyword><keyword>Radiography</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2003</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0021-972X (Print) 0021-972X (Linking)</isbn><accession-num>12915641</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/12915641</url></related-urls></urls><electronic-resource-num>10.1210/jc.2003-030036</electronic-resource-num></record></Cite></EndNote>(Makitie et al. 2003). Treatment usually occurs most rigorously during the child’s growth period and can consist of multiple daily phosphate intakes as well as twice daily intakes of 1,25(OH)D3 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW5nbGFydDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW5nbGFydDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE.DATA (Linglart et al. 2014). It comes with complications though. Although the vitamin D and phosphate improve the rickets, it often causesside-effects including hypercalcemia, nausea, vomiting, nephrocalcinosis, secondary hyperparathyroidism, and even higher FGF23 levels can occur PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Leifheit-Nestler et al. 2017; Liu et al. 2016a).
In an attempt to overcome some of the side-effects of using 1,25(OH)2D3, vVitamin D analogues are frequently used are a form of synthetic vitamin D and the three most common forms used in the treatment of XLH are Eldecalcitriol, Alfacalcidiol, and Calcitriol. For example, aAlphacalcidiol and calcitriol may be useful in lowering PTHnomralising biochemical parameters such as PTH in XLH patients. However, It has been shown to lower PTH effectively in patients with hyperparathyroidism and alleviate hyper parathyroid bone disease. It is risky though, hypercalcaemia remains a side-effect of alphacalcidiol treatment which, if sustained can lead to vascular and other soft tissue calcificationis likely and calcification of vascular tissue is a major risk. Experimentally, Eldecalcitriol (ED71) has been shown in the mosue model for XLH (HYP mice) to improve completely restored renal phosphate transport and Sodium-phosphate transporter protein levels in mice, despite levels of FGF23 increasing PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (Kido et al. 2013). The mice increased in weight, their bone mineral content and serum phsopajhte levels increased, and the growth plate structure was improved. Serum phosphate levels normalised and the total bone volume increased. ED71 does not treat the underlying FGF23 excess, but may be a useful treatment in XLH in the future PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (Kido et al. 2013), however, ED-71 also causes hypercalcemia in other studies related to osteoporosis-treatment.Many studies to propose vitamin D-related treatments for XLH have used the HYP mouse model as a homolog for XLH for proof-of-principle studies. This year, the FDA approved the use of an FGF23 antibody for use in XLH patients. Whilst beneficial in many aspects, there are many side effects that will make the treatment inappropriate for many patients. Mouse model for XLH: HYP mice were first discovered in Jackson Labs in 1966 and are now the well-established murine homolog for human XLH. The biochemical and skeletal responses to phosphate supplementation in HYP are very similar to human XLH patients and are thus a very valuable resource for researching this rare disease ADDIN EN.CITE <EndNote><Cite><Author>Eicher</Author><Year>1976</Year><RecNum>76</RecNum><DisplayText>(Eicher et al. 1976; Marie, Travers &amp; Glorieux 1981)</DisplayText><record><rec-number>76</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533032419″>76</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Eicher, E. M</author><author>Southard, J. L</author><author>Scriver, C. R</author><author>Glorieux, F. H.</author></authors></contributors><titles><title>Hypophosphatemia: Mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets</title><secondary-title>Proc Natl Acad Sci USA</secondary-title></titles><periodical><full-title>Proc Natl Acad Sci USA</full-title></periodical><pages>4667-4671</pages><volume>73</volume><number>12</number><dates><year>1976</year></dates><urls></urls></record></Cite><Cite><Author>Marie</Author><Year>1981</Year><RecNum>17</RecNum><record><rec-number>17</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519793688″>17</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P. J.</author><author>Travers, R.</author><author>Glorieux, F. H.</author></authors></contributors><titles><title>Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse</title><secondary-title>Journal of Clinical Investigation</secondary-title></titles><periodical><full-title>Journal of Clinical Investigation</full-title></periodical><pages>911-914</pages><volume>67</volume><number>3</number><dates><year>1981</year></dates><isbn>0021-9738</isbn><urls></urls><electronic-resource-num>10.1172/jci110110</electronic-resource-num></record></Cite></EndNote>(Eicher et al. 1976; Marie, Travers & Glorieux 1981). HYP mice display many of the same phenotypic traits such as hypophosphatemia, rickets, high serum alkaline phosphatase, slight modest hypocalcaemia, and marked reduction ined bone growth and mineralisation content ADDIN EN.CITE <EndNote><Cite><Author>Eicher</Author><Year>1976</Year><RecNum>76</RecNum><DisplayText>(Eicher et al. 1976; Marie, P.J, Travers, R &amp; Glorieux, F.H 1982)</DisplayText><record><rec-number>76</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533032419″>76</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Eicher, E. M</author><author>Southard, J. L</author><author>Scriver, C. R</author><author>Glorieux, F. H.</author></authors></contributors><titles><title>Hypophosphatemia: Mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets</title><secondary-title>Proc Natl Acad Sci USA</secondary-title></titles><periodical><full-title>Proc Natl Acad Sci USA</full-title></periodical><pages>4667-4671</pages><volume>73</volume><number>12</number><dates><year>1976</year></dates><urls></urls></record></Cite><Cite><Author>Marie</Author><Year>1982</Year><RecNum>16</RecNum><record><rec-number>16</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519792889″>16</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P.J</author><author>Travers, R</author><author>Glorieux, F.H</author></authors></contributors><titles><title>Bone Response to Phosphate and Vitamin D Metabolites in the Hypophosphatemic mouse model</title><secondary-title>Calcified Tissue International</secondary-title></titles><periodical><full-title>Calcified Tissue International</full-title></periodical><pages>158-164</pages><volume>34</volume><number>1</number><dates><year>1982</year></dates><urls></urls></record></Cite></EndNote>(Eicher et al. 1976; Marie, P.J, Travers, R & Glorieux, F.H 1982). FGF23 levels in HYP mice are up to 5 to 25- fold higher than in WT mice, and CYP24A1 levels are significantly elevated ADDIN EN.CITE <EndNote><Cite><Author>Azam</Author><Year>2003</Year><RecNum>4275</RecNum><DisplayText>(Azam et al. 2003)</DisplayText><record><rec-number>4275</rec-number><foreign-keys><key app=”EN” db-id=”5ardrpxr60pvfnef52axpsxpptazw02s9pvw” timestamp=”1253599893″>4275</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Azam, N.</author><author>Zhang, M. Y.</author><author>Wang, X.</author><author>Tenenhouse, H. S.</author><author>Portale, A. A.</author></authors></contributors><titles><title>Disordered regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase gene expression by phosphorus in X-linked hypophosphatemic (hyp) mice</title><secondary-title>Endocrinology</secondary-title></titles><periodical><full-title>Endocrinology</full-title><abbr-1>Endocrinology</abbr-1></periodical><pages>3463-8</pages><volume>144</volume><number>8</number><dates><year>2003</year></dates><label>22747512</label><urls></urls></record></Cite></EndNote>(Azam et al. 2003). Similarly to XLH patients, HYP mice display an “intestinal resistance” to vitamin D therapy and defective renal CYP27B1 activity ADDIN EN.CITE <EndNote><Cite><Author>Meyer</Author><Year>1996</Year><RecNum>15</RecNum><DisplayText>(Meyer, Meyer &amp; Morgan 1996)</DisplayText><record><rec-number>15</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519792619″>15</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Meyer, R.A</author><author>Meyer, M. H</author><author>Morgan, P.L</author></authors></contributors><titles><title><style face=”normal” font=”default” size=”100%”>Effects of Altered Diet on Serum levels of 1,25-Dihydroxyvitamin D and Parathyroid Hormone in X-Linked Hypophosphatemic </style><style face=”italic” font=”default” size=”100%”>(HYP and Gy) </style><style face=”normal” font=”default” size=”100%”>Mice</style></title><secondary-title>Bone</secondary-title></titles><periodical><full-title>Bone</full-title></periodical><pages>23-28</pages><volume>18</volume><number>1</number><dates><year>1996</year></dates><urls></urls></record></Cite></EndNote>(Meyer, Meyer & Morgan 1996). HYP mice have been reported to have low 1,25(OH)2D3 and 25(OH)D3 levels, and indeed, our group has also found this. More recent literature suggests that the disorder lies in the HYP kidney and that if the kidney were removed and replaced with a WT kidney, the hypophosphatemia would be rescued. It wasn’t ADDIN EN.CITE <EndNote><Cite><Author>Panda</Author><Year>2001</Year><RecNum>56</RecNum><DisplayText>(Panda et al. 2001)</DisplayText><record><rec-number>56</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533031870″>56</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Panda, D. K</author><author>Miao, D</author><author>Tremblay, M. L</author><author>Sirois, J</author><author>Farookhi, R</author><author>Hendy, G. N</author><author>Goltzman, D.</author></authors></contributors><titles><title>Targeted ablation of the 25-hydroxyvitamin D 1a-hydroxlylase enzyme: Evidence for skeletal, reproductive, and immune dysfunction</title><secondary-title>PNAS</secondary-title></titles><periodical><full-title>PNAS</full-title></periodical><pages>7498-7503</pages><volume>98</volume><number>13</number><dates><year>2001</year></dates><urls></urls></record></Cite></EndNote>(Panda et al. 2001). The focus therefore has moved to counteracting the effects of FGF23 excess PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW5nbGFydDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW5nbGFydDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE.DATA (Linglart et al. 2014). in recent unpublished observations.The mMajority of interventions on HYP mice have used tested the efficacy of either phosphate, 1,25(OH)D3, or a combination of the two.
Therapy with dietary Vitamin D: Williamson et al in 2017 demonstrated that when WT mice are fed 20,000IU/kg of vitamin D during their growth period, they had tougher bone that was more ductile and less brittle. They concluded that Vitamin D3 increases bone strength and peak bone mass PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxsaWFtc29uPC9BdXRob3I+PFllYXI+MjAxNzwvWWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxsaWFtc29uPC9BdXRob3I+PFllYXI+MjAxNzwvWWVh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ADDIN EN.CITE.DATA (Williamson et al. 2017). High dietary vitamin D in the order of 10-20,000IU has been shown to restore vitamin D regulated genes in the intestine and kidney of CYP27B1KO mice ADDIN EN.CITE <EndNote><Cite><Author>Rowling</Author><Year>2007</Year><RecNum>81</RecNum><DisplayText>(Rowling, Matthew J et al. 2007)</DisplayText><record><rec-number>81</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533113728″>81</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Rowling, Matthew J</author><author>Gliniak, Christy</author><author>Welsh, JoEllen</author><author>Fleet, James C</author></authors></contributors><titles><title>High dietary vitamin D prevents hypocalcemia and osteomalacia in CYP27B1 knockout mice</title><secondary-title>The Journal of nutrition</secondary-title></titles><periodical><full-title>The Journal of nutrition</full-title></periodical><pages>2608-2615</pages><volume>137</volume><number>12</number><dates><year>2007</year></dates><isbn>0022-3166</isbn><urls><related-urls><url>https://watermark.silverchair.com/2608.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAcAwggG8BgkqhkiG9w0BBwagggGtMIIBqQIBADCCAaIGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMpmD_KmwRd4sGvFgjAgEQgIIBc6dnUxoCZL1YaBZdkc2ucI5X1-RQfXvPZWKQ02OVcRZZvOFjl1Fz9SCa38bb7d0d5Vcljd1q1Vk8la1MlnM7PMUNOyzIRx45OQEB8TooskRO12tczIL0gsaABrtQppQkj0WZQua03_RzIAmUbsDWE_cdlbotQBj7iAISYqr0c1s7JT8xPz7I3tRf6i2QNLpI106GHBW_VJGveUsgo1UDr3ZvlVx0esTI587hPzZaRYsGaYI6NPZI5RqgjQoCMaIaIOfLdD2wB7r094DMgSOrQLtaGD3HUoBbsaJBgOX_Uq7WA3m4leOAGp2gsvWHh8zXyWH4bzJZP6Rcb_Y1m4T4pRO_jRrFNDOngvpP-REW63Mx55_cj3vzDYXc8J7Erzi-NMh47kE2n53mnes4hDMin3TpPqg0LV9f958aKTvcVHdD1ih-kicgSYa12aDVlKfjb3hpP90p13eZfJh3dvEDS8OmEgBaLHu9TbopBiELK2nrEm-4</url></related-urls></urls></record></Cite></EndNote>(Rowling, Matthew J et al. 2007). This suggests that if given in a high enough dose, vitamin D can overcome a lack of CYP27B1 activity in the kidney and even normalise calcium levels. Very high levels of 25(OH)D3, the inactive prohormone, can also influence calcium and bone metabolism independent of its conversion to 1,25(OH)D3 ADDIN EN.CITE <EndNote><Cite><Author>Rowling</Author><Year>2007</Year><RecNum>81</RecNum><DisplayText>(Rowling, Matthew J et al. 2007)</DisplayText><record><rec-number>81</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533113728″>81</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Rowling, Matthew J</author><author>Gliniak, Christy</author><author>Welsh, JoEllen</author><author>Fleet, James C</author></authors></contributors><titles><title>High dietary vitamin D prevents hypocalcemia and osteomalacia in CYP27B1 knockout mice</title><secondary-title>The Journal of nutrition</secondary-title></titles><periodical><full-title>The Journal of nutrition</full-title></periodical><pages>2608-2615</pages><volume>137</volume><number>12</number><dates><year>2007</year></dates><isbn>0022-3166</isbn><urls><related-urls><url>https://watermark.silverchair.com/2608.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAcAwggG8BgkqhkiG9w0BBwagggGtMIIBqQIBADCCAaIGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMpmD_KmwRd4sGvFgjAgEQgIIBc6dnUxoCZL1YaBZdkc2ucI5X1-RQfXvPZWKQ02OVcRZZvOFjl1Fz9SCa38bb7d0d5Vcljd1q1Vk8la1MlnM7PMUNOyzIRx45OQEB8TooskRO12tczIL0gsaABrtQppQkj0WZQua03_RzIAmUbsDWE_cdlbotQBj7iAISYqr0c1s7JT8xPz7I3tRf6i2QNLpI106GHBW_VJGveUsgo1UDr3ZvlVx0esTI587hPzZaRYsGaYI6NPZI5RqgjQoCMaIaIOfLdD2wB7r094DMgSOrQLtaGD3HUoBbsaJBgOX_Uq7WA3m4leOAGp2gsvWHh8zXyWH4bzJZP6Rcb_Y1m4T4pRO_jRrFNDOngvpP-REW63Mx55_cj3vzDYXc8J7Erzi-NMh47kE2n53mnes4hDMin3TpPqg0LV9f958aKTvcVHdD1ih-kicgSYa12aDVlKfjb3hpP90p13eZfJh3dvEDS8OmEgBaLHu9TbopBiELK2nrEm-4</url></related-urls></urls></record></Cite></EndNote>(Rowling, Matthew J et al. 2007). Therapy with injections of 1,25(OH)D3 or FGF23 Antibodies: Daily injections of 1,25(OH)2D3 and/or FGF23 antibody in HYP mice were shown to improve cortical microarchitecture and whole bone biomechanical properties PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Liu et al. 2016a). The daily treatment of 1,25(OH)2D3 also led to a decrease in urine phosphate wasting despite the increasing FGF23 levels. Mice had normocalcaemia, normal PTH, and increased serum phosphate levels. The sodium-phosphate transporters in the gut were upregulated, and body weight increased. The bone growth plate and metaphyseal organisation were improved, along with the lumbar vertebral height, and trabecular structure PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Liu et al. 2016a). However, 1,25(OH)2D3 treatment at this scale in humans would cause hypercalcaemia and nephrocalcinosis.

Only one previous Researchers have treated HYP mice with FGF23 antibodies and found a correction in the phosphate and vitamin D levels, an increase in function of sodium-phosphate cotransporters, and suppressed CYP24A1 expression in the kidney. Antibodies administered during the growth phase had the best effect and resulted in elongation of the femur, improved mineralisation, and normalised cartilage development PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bb25vPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bb25vPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (Aono et al. 2009).Therapy with 25D: Onlystudy has used one very old study from 1982 used the inactive from of vitamin D, 25(OH)D3, to try rescue the bone phenotype ADDIN EN.CITE <EndNote><Cite><Author>Marie</Author><Year>1982</Year><RecNum>80</RecNum><DisplayText>(Marie, P. J, Travers, R &amp; Glorieux, F. H 1982)</DisplayText><record><rec-number>80</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533113679″>80</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P. J</author><author>Travers, R</author><author>Glorieux, F. H</author></authors></contributors><titles><title>Healing of bone lesions with 1, 25-dihydroxyvitamin D3 in the young X-linked hypophosphatemic male mouse</title><secondary-title>Endocrinology</secondary-title></titles><periodical><full-title>Endocrinology</full-title></periodical><pages>904-911</pages><volume>111</volume><number>3</number><dates><year>1982</year></dates><isbn>0013-7227</isbn><urls><related-urls><url><style face=”underline” font=”default” size=”100%”>https://academic.oup.com/endo/article-abstract/111/3/904/2591271?redirectedFrom=fulltext</style></url></related-urls></urls></record></Cite></EndNote>(Marie, P. J, Travers, R & Glorieux, F. H 1982). Marie et al infused a very relatively low doses of 25(OH)D3 into HYP mice over a 3 week period,. iIn addition to phosphate salts in the drinking water., the While 25(OH)D3 levels were shown to marginally improve, the underminerlised bone improved the serum calcium and phosphate levels, and suppressed bone turnover. Despite the normalisation in serum parameters, osteomalacia persisted. This suggested to the authors that there is was a specific bone cell resistance to mineral and/or hormonal treatment ADDIN EN.CITE <EndNote><Cite><Author>Marie</Author><Year>1982</Year><RecNum>16</RecNum><DisplayText>(Marie, P.J, Travers, R &amp; Glorieux, F.H 1982)</DisplayText><record><rec-number>16</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519792889″>16</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P.J</author><author>Travers, R</author><author>Glorieux, F.H</author></authors></contributors><titles><title>Bone Response to Phosphate and Vitamin D Metabolites in the Hypophosphatemic mouse model</title><secondary-title>Calcified Tissue International</secondary-title></titles><periodical><full-title>Calcified Tissue International</full-title></periodical><pages>158-164</pages><volume>34</volume><number>1</number><dates><year>1982</year></dates><urls></urls></record></Cite></EndNote>(Marie, P.J, Travers, R & Glorieux, F.H 1982). While this conclusion may be true, no further investigations have been performed to elevate 25(OH)D to levels that, more recently, have shown to improve bone mineralisation in other settings. For example, 20,000IU/kg of vitamin D fed to mice resulting increased bone mineralisation and stronger bones without causing hypercalcemia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxsaWFtc29uPC9BdXRob3I+PFllYXI+MjAxNzwvWWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxsaWFtc29uPC9BdXRob3I+PFllYXI+MjAxNzwvWWVh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ADDIN EN.CITE.DATA (Williamson et al. 2017).The role of vitamin D catabolism in XLH25(OH)D3, and indeed 24,25(OH)D3, are often used in conjunction with 1,25D treatment in XLH patients despite little evidence of benefits, and unfortunately there is no further literature about 25(OH)D3 supplementation in HYP mice. We hypothesise that if we are able to increase 25(OH)D3 levels high enough in HYP mice by feeding or infusing at even higher doses, we may begin to overcome any disorder of CYP27B1 in the kidney, or phosphate wasting in the gut. Increasing phosphate and 1,25(OH)D3 supplementation again and again would only increase phosphate wasting, FGF23, PTH, and the risk of hypercalcaemia. We aim to raise 25(OH)D3 levels by feeding the parent calciferols or infusing the inactive metabolite 25(OH)D3.CInhibition of CYP24A1YP24A1 is the sole enzyme involved in the catabolism of vitamin D. While the classical view is that CYP24A1 limits the tissue activity of 1,25(OH)2D, renal CYP24A1 activity has been shown to regulate circulating 1,25(OH)2D levels which also impacts tissue-level activity as well (Anderson et al 2004). Furthermore, in bone CYP24A1 activity has been shown to be regulated independently of circulating 1,25(OH)2D levels, indicating that autocrine regulation of 1,25(OH)2D activity in bone is independent or renal vitamin D metabolism regulation (Anderson et al 2005). We have recently also demonstrated that the genetic deletion of CYP24A1 in osteocytes using Cre-lox technology, increases bone volume in young mice suggesting that the CYP24A1 in osteocytes plays an inhibitory role on bone mineralisation (Barratt et al, in preparation).
In Hyp mice, renal CYP24A1 levels have been shown to be 2-fold higher in HYP mice ADDIN EN.CITE <EndNote><Cite><Author>Azam</Author><Year>2003</Year><RecNum>4275</RecNum><DisplayText>(Azam et al. 2003)</DisplayText><record><rec-number>4275</rec-number><foreign-keys><key app=”EN” db-id=”5ardrpxr60pvfnef52axpsxpptazw02s9pvw” timestamp=”1253599893″>4275</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Azam, N.</author><author>Zhang, M. Y.</author><author>Wang, X.</author><author>Tenenhouse, H. S.</author><author>Portale, A. A.</author></authors></contributors><titles><title>Disordered regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase gene expression by phosphorus in X-linked hypophosphatemic (hyp) mice</title><secondary-title>Endocrinology</secondary-title></titles><periodical><full-title>Endocrinology</full-title><abbr-1>Endocrinology</abbr-1></periodical><pages>3463-8</pages><volume>144</volume><number>8</number><dates><year>2003</year></dates><label>22747512</label><urls></urls></record></Cite></EndNote>(Azam et al. 2003) which contributes to lower circulating 1,25(OH)2D levels. No investigations have yet been performed to demonstrate whether osteocytic CYP24A1 levels are in increased in Hyp mice. However, it is unclear whether the bones of HYP mice have aberrantly high CYP24A1, which would frustrate the anabolic activities of 1,25(OH)2D. It is worth noting however, that low phosphate levels may directly contribute to the high expression of CYP24A1, in osteocytes at least, given that decreasing phosphate levels in media of the osteocyte cell line, IDG-SW3, enhances the induction of Cyp24a1 by 1,25(OH)2D ADDIN EN.CITE <EndNote><Cite><Author>Ito</Author><Year>2013</Year><RecNum>1</RecNum><DisplayText>17</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app=”EN” db-id=”r9a0z5fzo02xtzexaf6v552vztvxfwwfexdp” timestamp=”1455686794″>1</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Ito, N.</author><author>Findlay, D. M.</author><author>Anderson, P. H.</author><author>Bonewald, L. F.</author><author>Atkins, G. J.</author></authors></contributors><auth-address>Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide 5005, Australia.</auth-address><titles><title>Extracellular phosphate modulates the effect of 1alpha,25-dihydroxy vitamin D3 (1,25D) on osteocyte like cells</title><secondary-title>J Steroid Biochem Mol Biol</secondary-title><alt-title>The Journal of steroid biochemistry and molecular biology</alt-title></titles><periodical><full-title>J Steroid Biochem Mol Biol</full-title><abbr-1>The Journal of steroid biochemistry and molecular biology</abbr-1></periodical><alt-periodical><full-title>J Steroid Biochem Mol Biol</full-title><abbr-1>The Journal of steroid biochemistry and molecular biology</abbr-1></alt-periodical><pages>183-6</pages><volume>136</volume><keywords><keyword>Animals</keyword><keyword>Calcitriol/metabolism/*pharmacology</keyword><keyword>Cell Differentiation/drug effects</keyword><keyword>Cell Line</keyword><keyword>Extracellular Space/chemistry/*physiology</keyword><keyword>Mice</keyword><keyword>Osteocytes/cytology/*drug effects/*metabolism</keyword><keyword>Osteogenesis/*drug effects/physiology</keyword><keyword>Phosphates/chemistry/*physiology</keyword></keywords><dates><year>2013</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1879-1220 (Electronic) 0960-0760 (Linking)</isbn><accession-num>23064198</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/23064198</url></related-urls></urls><electronic-resource-num>10.1016/j.jsbmb.2012.09.029</electronic-resource-num></record></Cite></EndNote>17. Furthermore, HYP primary osteocytes exposed to 1,25(OH)2D do not induce mRNA levels for vitamin D responsive genes such as VDR or Fgf23 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaXlhZ2F3YTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaXlhZ2F3YTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE.DATA 18, perhaps suggesting that excessive CYP24A1 catabolises 1,25(OH)2D. However, the authors of this study did not directly measure CYP24A1 or 1,25(OH)2D clearance (Prof T. Michigami, personal communications). Regardless, these data suggest that Cyp24a1 activity in bone, possibly osteoblasts, osteocytes or chondrocytes during phosphate wasting disorders, may reduce 1,25D activity in bone, resulting in under-mineralisation. A recent key study in investigating the role of CYP24A1 in HYP mice was performed by crossing the global CYP24A1-knockout mice with HYP mice. The hypothesis was that the absence of CYP24A1 would elevate circulating 1,25(OH)2D levels and contribute to the healing of the XLH bone phenotype. To the surprise of the authors, the absence of CYP24A1 resulted in the complete prevention of growth and mineralisation disorder in HYP mice ADDIN EN.CITE <EndNote><Cite><Author>Bai</Author><Year>2016</Year><RecNum>7956</RecNum><DisplayText>(Bai et al. 2016)</DisplayText><record><rec-number>7956</rec-number><foreign-keys><key app=”EN” db-id=”5ardrpxr60pvfnef52axpsxpptazw02s9pvw” timestamp=”1472745196″>7956</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Bai, X.</author><author>Miao, D.</author><author>Xiao, S.</author><author>Qiu, D.</author><author>St-Arnaud, R.</author><author>Petkovich, M.</author><author>Gupta, A.</author><author>Goltzman, D.</author><author>Karaplis, A. C.</author></authors></contributors><titles><title>CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders</title><secondary-title>J Clin Invest</secondary-title></titles><periodical><full-title>Journal of Clinical Investigations</full-title><abbr-1>J Clin Invest</abbr-1></periodical><pages>667-80</pages><volume>126</volume><number>2</number><keywords><keyword>Animals</keyword><keyword>Cytochrome P-450 Enzyme Inhibitors/*pharmacology</keyword><keyword>Disease Models, Animal</keyword><keyword>Female</keyword><keyword>Fibroblast Growth Factors/genetics/*metabolism</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Mice, Knockout</keyword><keyword>Phosphates/*urine</keyword><keyword>*Renal Insufficiency, Chronic/drug therapy/genetics/pathology/urine</keyword><keyword>Vitamin D3 24-Hydroxylase/*antagonists &amp; inhibitors/genetics/metabolism</keyword><keyword>*Wasting Syndrome/drug therapy/genetics/pathology/urine</keyword></keywords><dates><year>2016</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1558-8238 (Electronic) 0021-9738 (Linking)</isbn><accession-num>26784541</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/26784541</url></related-urls></urls><custom2>PMC4731193</custom2><electronic-resource-num>10.1172/JCI81928</electronic-resource-num></record></Cite></EndNote>(Bai et al. 2016). Interestingly, while growth plate and cortical bone mineral was restored, the key biochemical indices of HYP disorder, namely hypophosphatemia and low 1,25(OH)2D levels, remained low and unchanged. These exciting data suggest that the current therapy of correcting blood phosphate and circulating 1,25(OH)2D is not essential to normalise bone health in XLH. Furthermore, these data suggest that CYP24A1 deletion in tissues other than the kidney, play a major role in allowing normal bone mineral levels. Given the evidence for the role of CYP24A1 in bone homeostasis, a key tissue to investigate further is the bone with respect to CYP24A1 and its role in XLH.

RESAERCH DESIGN: AIMS AND METHODS:Model 1Model 2Aim 1: To determine whether raising levels of 25(OH)D3 in HYP mice improves the bone phenotypeMale HYP miceDietary feedingn=12 per group4 groups= total of 48 miceOsmotic pumpsn=6 per group3 groups=total 18 miceAim 2: The role of CYP24A1 inhibition in XLHMale HYP-OBCYP24KODietary feedingn=12 per group4 groups= total of 48 miceOsmotic pumpsn=6 per group3 groups=total 18 miceAim 1: To determine whether raising circulating 25-hydroxyvitamin D (25D) levels heal the bone in Hyp mice.Aim 1: To determine whether raising levels of 25(OH)D3 in HYP mice improves the bone phenotypeRationale: The disorder of XLH, was previously known as vitamin D-resistant rickets owing to the fact the renal conversion of 25(OH)D3 to 1,25(OH)D3 was impeded by FGF23. We know that bone is a major site for local synthesis and activity of 1,25(OH)D3 and is dependent on the circulating supply of 25(OH)D3. There have been no previous studies to examine whether raising 25(OH)D3 to high levels through dietary vitamin D administration can heal the bone phenotype more easily than 1,25(OH)D3. Thus, it is valuable to assess whether the HYP bone can be healed through raising the serum 25(OH)D levels either by dietary vitamin D supplementation or direct infusion of 25(OH)D.

Model 1: Male HYP (XHypY) mice will be supplemented with vitamin D from 3 weeks of age until 12 weeks of age. Mice (n=12/grp) will receive diets containing 1000 IU/kg (standard) or 20,000IU/kg of vitamin D plus either 0.625% phosphorus (standard) or 1.25% phosphorus (high). These levels of vitamin D should significantly raise 25(OH)D3 levels to an approximate maximum of 200 nmol/L without causing direct activation of the VDR ADDIN EN.CITE <EndNote><Cite><Author>Rowling</Author><Year>2007</Year><RecNum>6750</RecNum><DisplayText>(Rowling, M. J. et al. 2007)</DisplayText><record><rec-number>6750</rec-number><foreign-keys><key app=”EN” db-id=”5ardrpxr60pvfnef52axpsxpptazw02s9pvw” timestamp=”1253599895″>6750</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Rowling, M. J.</author><author>Gliniak, C.</author><author>Welsh, J.</author><author>Fleet, J. C.</author></authors></contributors><auth-address>Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556 4Interdepartmental Nutrition Program and Department of Foods and Nutrition, Purdue University, West Lafayette, IN 47906.</auth-address><titles><title>High Dietary Vitamin D Prevents Hypocalcemia and Osteomalacia in CYP27B1 Knockout Mice</title><secondary-title>J Nutr</secondary-title></titles><pages>2608-15</pages><volume>137</volume><number>12</number><dates><year>2007</year><pub-dates><date>Dec</date></pub-dates></dates><accession-num>18029472</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=18029472</url></related-urls></urls></record></Cite></EndNote>(Rowling, M. J. et al. 2007).

Model 2; Male HYP (XHypY) mice will be fed a standard level of phosphorus from 3 weeks of age until 8 weeks of age. At 4 weeks of age, mice will undergo minor surgery to insert a mini osmotic pump (Alzet 1004) subcutaneously containing 25(OH)D3 (100ng or 200ng/day), or saline, at a constant rate over a 4 week period.
At time of death, we will collect tissues and employ our suite of established analyses described in previous publications PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmRlcnNvbjwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmRlcnNvbjwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+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==
ADDIN EN.CITE.DATA 23, 26, 36. Biochemical analyses: serum levels of calcium, phosphate, ALP (Kone Chemistry Analyser), 25(OH)D3 and 1,25(OH)D3 (LC-MS/MS), PTH, and intact FGF23 (commercially available ELISA assays). Ex-vivo micro-CT analyses: For Model 1,femoral and vertebral scans will be performs as per laboratory SOPs. This provides a non-destructive 3D image of the inner bone structure and allows for evaluation of the treatment on bone health. and regions of interest (ROI) adjusted based on the average femur length for each of the groups. In vivo micro-CT analyses: For Model 2, 2 weeks post-surgery (6 weeks of age), mice will be anaesthetised for a lower-leg micro-CT scan (Skyscan 1276). This provides a non-destructive 3D image of the inner bone structure and allows a mid-treatment evaluation of the treatment on bone health. Tissue histology and histomorphometric analyses: To evaluate mineralisation, sections of the left femur (after microCT scanning) will be embedded in methylmethacrylate before sectioning. Histomorphometry will use Osteomeasure (Osteometrics), in accordance to criteria of the American Society of Bone and Mineral Research ADDIN EN.CITE <EndNote><Cite><Author>Dempster</Author><Year>2013</Year><RecNum>93</RecNum><DisplayText>(Dempster et al. 2013)</DisplayText><record><rec-number>93</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1534470947″>93</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Dempster, D. W.</author><author>Compston, J. E.</author><author>Drezner, M. K.</author><author>Glorieux, F. H.</author><author>Kanis, J. A.</author><author>Malluche, H.</author><author>Meunier, P. J.</author><author>Ott, S. M.</author><author>Recker, R. R.</author><author>Parfitt, A. M.</author></authors></contributors><auth-address>Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, NY, USA. [email protected]</auth-address><titles><title>Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee</title><secondary-title>J Bone Miner Res</secondary-title></titles><periodical><full-title>J Bone Miner Res</full-title></periodical><pages>2-17</pages><volume>28</volume><number>1</number><edition>2012/12/01</edition><keywords><keyword>Animals</keyword><keyword>Bone and Bones/*anatomy &amp; histology</keyword><keyword>Guidelines as Topic</keyword><keyword>Humans</keyword><keyword>Reference Standards</keyword><keyword>*Research Report</keyword><keyword>*Terminology as Topic</keyword></keywords><dates><year>2013</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1523-4681 (Electronic) 0884-0431 (Linking)</isbn><accession-num>23197339</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/23197339</url></related-urls></urls><custom2>PMC3672237</custom2><electronic-resource-num>10.1002/jbmr.1805</electronic-resource-num></record></Cite></EndNote>(Dempster et al. 2013), and include measures of bone formation (dual fluorochrome labelling prior to death), osteoid volume and growth plate height (Massons’-Goldner’s Modified Trichrome), osteoblast surface (toluidine blue staining), and osteoclasts (TRAP stain). Messenger RNA analyses: Soft tissues will be snap frozen and RNA extracted using the TRIZOL RNA isolation protocol. cDNA will be synthesised for the purpose of RT PCR’s. Relative expression of CYP24A1, CYP27B1, NaPi2a, NaPi2c, CYP2R1 and CYP24A1 will be reported.

Outcomes
This study is a necessary dietary intervention for HYP mice that frankly should have been done years ago. It will assess if there is resistance to vitamin D synthesis and activity in the bone of HYP mice, be it due to excessive FGF23 or another factor, even with high circulating levels of 25(OH)D and dietary phosphate supplementation.

Aim 2: To determine whether raising osteocyte levels of active vitamin D (1,25(OH)2D) heals the bone of Hyp mice.Rationale: As discussed above, global deletion of CYP24A1 heals the under-mineralised and disturbed growth plate phenotype in HYP mice. This occurs despite the persistence of hypophosphataemia and an even lower serum 1,25(OH)D levels ADDIN EN.CITE <EndNote><Cite><Author>Bai</Author><Year>2016</Year><RecNum>42</RecNum><DisplayText>15</DisplayText><record><rec-number>42</rec-number><foreign-keys><key app=”EN” db-id=”r9a0z5fzo02xtzexaf6v552vztvxfwwfexdp” timestamp=”1455689710″>42</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Bai, X.</author><author>Miao, D.</author><author>Xiao, S.</author><author>Qiu, D.</author><author>St-Arnaud, R.</author><author>Petkovich, M.</author><author>Gupta, A.</author><author>Goltzman, D.</author><author>Karaplis, A. C.</author></authors></contributors><titles><title>CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders</title><secondary-title>J Clin Invest</secondary-title></titles><periodical><full-title>J Clin Invest</full-title></periodical><pages>667-80</pages><volume>126</volume><number>2</number><dates><year>2016</year><pub-dates><date>Feb 1</date></pub-dates></dates><isbn>1558-8238 (Electronic) 0021-9738 (Linking)</isbn><accession-num>26784541</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/26784541</url></related-urls></urls><custom2>PMC4731193</custom2><electronic-resource-num>10.1172/JCI81928</electronic-resource-num></record></Cite></EndNote>15. These data demonstrate that low serum phosphate and low circulating 1,25D levels are not primarily responsible for the under-mineralisation. While strongly suggestive, the limitation of this study is the inability to definitively implicate bone CYP24A1. The two most likely candidate cell-types in bone that are responsible for the HYP bone phenotype are osteocytes or chondrocytes. Both cell-types have been shown to produce FGF23, control phosphate homeostasis, and are involved in process of bone formation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXN1eWFtYTwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXN1eWFtYTwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+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ADDIN EN.CITE.DATA 38. Thus, to determine whether abrogating Cyp24a1 activity in bone improves the bone phenotype of the HYP mice, conditional knockout mouse models are required. We will utilise Cre-lox systems to delete Cyp24a1 in osteocytes. We have previously created the osteocyte-specific CYP24A1KO mice. These mice will be crossed with HYP mice to determine whether the absence of Cyp24a1 activity in either osteoblast/osteocytes or chondrocytes in HYP mice is capable of promoting mineralisation and overcoming bone under-mineralisation.

Model: Our team has previously created the floxed Cyp24a1 (Cyp24a1flox/+) and OcyCYP24KO (OcyCyp24a1-/-) mouse models. Male HYP mice are far less virile that the females so generation of a HYP mouse in which Cyp24a1 has been specifically deleted in osteocytes (HYP/OcyCyp24a1-/-) requires a particular breeding strategy. Heterozygous female HYP (XXHyp) will be crossed with Cyp24a1flox/flox males to obtain HYP/Cyp24a1flox/+ double heterozygous females. Then HYP/Cyp24a1flox/+ females will be crossed with Cyp24a1flox/flox males to generate HYP/Cyp24a1flox/flox females. Finally, HYP/Cyp24a1flox/flox females will be crossed with OcyCyp24a1-/+ males to obtain the osteoblast/osteocyte-specific deletion of Cyp24a1 in HYP mice. Studies will include the following four genotypes: Cyp24a1flox/+ (wild-type equivalent) control, OcyCyp24a1-/-, HYP (XHypY), and compound HYP/OcyCyp24a1-/- male littermates as well as Cyp24a1flox/- and HYP/Cyp24a1flox/- male mice.

Male HYP (XHypY) mice will be supplemented with vitamin D from 3 weeks of age until 12 weeks of age (as in Aim 1, Model 1), and infused with 25(OH)D (as in Aim 1, Model 2).
At time of death, analyses will include Biochemical analyses,ex-vivo micro-CT analyses, in vivo micro-CT analyses, tissue histology and histomorphometric analyses and messenger RNA analyses as described in Aim 1.

Outcomes: Central to the hypothesis of this project is whether the absence of CYP24A1 activity within osteoblasts/osteocytes as well as chondrocytes enhances healing of bone in HYP mice, despite their elevated levels of FGF23. Examining HYP/conditional CYP24A1KO mice in the context of 25(OH)D supplementation, phosphorus supplementation and 1,25(OH)2D administration will reveal the importance of raised 1,25D within the key bone cell types in this context of healing HYP bone. As well, using definitive in vitro cell models will determine whether the absence of osteoblastic/osteocytic or chondrocytic Cyp24a1 activity alters differentiation and/or apoptosis of HYP cells independently of confounding factors that could occur in the in vivo studies. At the same time these in vitro studies will seek to establish whether key players in inhibiting mineralisation (such as ASARM peptides and sclerostin) are modulated by vitamin D, phosphate and/or CYP24A1 deletion. These studies will provide important insights into targeting CYP24A1 activity in bone in the condition of XLH.

.GANTT CHART AND PLANNED PUBLICATIONS:201820192020Tasks/MilestonesMAMJJASONDJFMAMJJASONDJFMEthics approval process                         RESA ‘Continuing to Completing’ series                         Literature review                         Animal research Aim 1                         Data analysis Aim 1                         Write up Aim 1                         Animal research Aim 2                         Data analysis Aim 2                         Write up Aim 2                         Submission                         Osteoblast Specific deletion of CYP24 data to be published in conjunction with data from the research team- Publish 2018HYP Aim 1: To determine whether raising levels of 25(OH)D3 in HYP mice improves the bone phenotype- Publish 2020HYP Aim 2: The role of CYP24A1 inhibition in XLH- Publish 2021REFERENCES:
ADDIN EN.REFLIST Azam, N, Zhang, MY, Wang, X, Tenenhouse, HS & Portale, AA 2003, ‘Disordered regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase gene expression by phosphorus in X-linked hypophosphatemic (hyp) mice’, Endocrinology, vol. 144, no. 8, pp. 3463-3468.

Bai, X, Miao, D, Xiao, S, Qiu, D, St-Arnaud, R, Petkovich, M, Gupta, A, Goltzman, D & Karaplis, AC 2016, ‘CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders’, Journal of Clinical Investigations, vol. 126, no. 2, Feb, pp. 667-680.

Carpenter, TO, Imel, EA, Holm, IA, Jan de Beur, SM & Insogna, KL 2011, ‘A clinician’s guide to X-linked hypophosphatemia’, J Bone Miner Res, vol. 26, no. 7, Jul, pp. 1381-1388.

Che, H, Roux, C, Etcheto, A, Rothenbuhler, A, Kamenicky, P, Linglart, A & Briot, K 2016, ‘Impaired quality of life in adults with X-linked hypophosphatemia and skeletal symptoms’, Eur J Endocrinol, vol. 174, no. 3, Mar, pp. 325-333.

David, V & Wolf, M 2016, ‘Pruning the ricket thicket’, J Clin Invest, vol. 126, no. 2, Feb, pp. 473-476.

Dempster, DW, Compston, JE, Drezner, MK, Glorieux, FH, Kanis, JA, Malluche, H, Meunier, PJ, Ott, SM, Recker, RR & Parfitt, AM 2013, ‘Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee’, J Bone Miner Res, vol. 28, no. 1, Jan, pp. 2-17.

Eicher, EM, Southard, JL, Scriver, CR & Glorieux, FH 1976, ‘Hypophosphatemia: Mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets’, Proc Natl Acad Sci USA, vol. 73, no. 12, pp. 4667-4671.

Erben, RG 2017, ‘Pleiotropic Actions of FGF23’, Toxicol Pathol, vol. 45, no. 7, Oct, pp. 904-910.

Kido, S, Kaneko, I, Tatsumi, S, Segawa, H & Miyamoto, K 2013, ‘Vitamin D and type II sodium-dependent phosphate cotransporters’, Contrib Nephrol, vol. 180, pp. 86-97.

Ko, FC, Martins, JS, Reddy, P, Bragdon, B, Hussein, AI, Gerstenfeld, LC & Demay, MB 2016, ‘Acute Phosphate Restriction Impairs Bone Formation and Increases Marrow Adipose Tissue in Growing Mice’, J Bone Miner Res, vol. 31, no. 12, Dec, pp. 2204-2214.

Leifheit-Nestler, M, Kucka, J, Yoshizawa, E, Behets, G, D’Haese, P, Bergen, C, Meier, M, Fischer, DC & Haffner, D 2017, ‘Comparison of calcimimetic R568 and calcitriol in mineral homeostasis in the Hyp mouse, a murine homolog of X-linked hypophosphatemia’, Bone, vol. 103, Oct, pp. 224-232.

Linglart, A, Biosse-Duplan, M, Briot, K, Chaussain, C, Esterle, L, Guillaume-Czitrom, S, Kamenicky, P, Nevoux, J, Prie, D, Rothenbuhler, A, Wicart, P & Harvengt, P 2014, ‘Therapeutic management of hypophosphatemic rickets from infancy to adulthood’, Endocr Connect, vol. 3, no. 1, pp. R13-30.

Liu, ES, Martins, JS, Raimann, A, Chae, BT, Brooks, DJ, Jorgetti, V, Bouxsein, ML & Demay, MB 2016a, ‘1,25-Dihydroxyvitamin D Alone Improves Skeletal Growth, Microarchitecture, and Strength in a Murine Model of XLH, Despite Enhanced FGF23 Expression’, J Bone Miner Res, vol. 31, no. 5, May, pp. 929-939.

Liu, ES, Martins, JS, Raimann, A, Chae, BT, Brooks, DJ, Jorgetti, V, Bouxsein, ML & Demay, MB 2016b, ‘1,25-Dihydroxyvitamin D Alone Improves Skeletal Growth, Microarchitecture and Strength in a Murine Model of XLH, Despite Enhanced FGF23 Expression’, J Bone Miner Res, Jan 11.

Makitie, O, Doria, A, Kooh, SW, Cole, WG, Daneman, A & Sochett, E 2003, ‘Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets’, J Clin Endocrinol Metab, vol. 88, no. 8, Aug, pp. 3591-3597.

Marie, PJ, Travers, R & Glorieux, FH 1981, ‘Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse’, Journal of Clinical Investigation, vol. 67, no. 3, pp. 911-914.

Marie, PJ, Travers, R & Glorieux, FH 1982, ‘Bone Response to Phosphate and Vitamin D Metabolites in the Hypophosphatemic mouse model’, Calcified Tissue International, vol. 34, no. 1, pp. 158-164.

Marie, PJ, Travers, R & Glorieux, FH 1982, ‘Healing of bone lesions with 1, 25-dihydroxyvitamin D3 in the young X-linked hypophosphatemic male mouse’, Endocrinology, vol. 111, no. 3, pp. 904-911.

Marie, PJ, Travers, R & Glorieux, FH 1982, ‘Healing of bone lesions with 1,25-dihydroxyvitamin D3 in the young X-linked hypophosphatemic male mouse’, Endocrinology, vol. 111, no. 3, Sep, pp. 904-911.

Meyer, RA, Meyer, MH & Morgan, PL 1996, ‘Effects of Altered Diet on Serum levels of 1,25-Dihydroxyvitamin D and Parathyroid Hormone in X-Linked Hypophosphatemic (HYP and Gy) Mice’, Bone, vol. 18, no. 1, pp. 23-28.

Portale, AA, Perwad, F & Miller, WL 2012, ‘Rickets Due to Hereditary Abnormalities of Vitamin D Synthesis or Action’, Pediatric Bone, pp. 679-698.

Roizen, JD, Li, D, O’Lear, L, Javaid, MK, Shaw, NJ, Ebeling, PR, Nguyen, HH, Rodda, CP, Thummel, KE, Thacher, TD, Hakonarson, H & Levine, MA 2018, ‘CYP3A4 mutation causes vitamin D-dependent rickets type 3’, J Clin Invest, vol. 128, no. 5, May 1, pp. 1913-1918.

Rowling, MJ, Gliniak, C, Welsh, J & Fleet, JC 2007, ‘High dietary vitamin D prevents hypocalcemia and osteomalacia in CYP27B1 knockout mice’, The Journal of nutrition, vol. 137, no. 12, pp. 2608-2615.

Rowling, MJ, Gliniak, C, Welsh, J & Fleet, JC 2007, ‘High Dietary Vitamin D Prevents Hypocalcemia and Osteomalacia in CYP27B1 Knockout Mice’, J Nutr, vol. 137, no. 12, Dec, pp. 2608-2615.

Williamson, L, Hayes, A, Hanson, ED, Pivonka, P, Sims, NA & Gooi, JH 2017, ‘High dose dietary vitamin D3 increases bone mass and strength in mice’, Bone Rep, vol. 6, Jun, pp. 44-50.

GANTT CHART AND PLANNED PUBLICATIONS:201820192020Tasks/MilestonesMAMJJASONDJFMAMJJASONDJFMEthics approval process                         RESA ‘Continuing to Completing’ series                         Literature review                         Animal research Aim 1                         Data analysis Aim 1                         Write up Aim 1                         Animal research Aim 2                         Data analysis Aim 2                         Write up Aim 2                         Submission                         

x

Hi!
I'm Piter!

Would you like to get a custom essay? How about receiving a customized one?

Check it out