Impact of Vitamin D Therapy in treating X-linked hypophosphatemic rickets Kate Barratt Research Proposal For the degree of Masters by Research

Impact of Vitamin D Therapy in treating X-linked hypophosphatemic ricketsKate BarrattResearch ProposalFor the degree of Masters by Research (Medical Science)SupervisorsAssociate Professor Paul AndersonProfessor Gerald AtkinsProfessor Howard MorrisOUTLINE: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 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ADDIN EN.CITE 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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 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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. outi.

[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 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 ADDIN EN.CITE 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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 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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 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ADDIN EN.CITE 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ADDIN EN.CITE.DATA (Liu et al. 2016a).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 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ADDIN EN.CITE 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ADDIN EN.

CITE.DATA (Ohata et al. 2014). Converse to effects of FGF23 excess disorders, if FGF23 is ablated, hyperphosphatemia and hypophosphaturia result PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaXRhcmE8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxSZWNOdW0+NTk8L1JlY051bT48RGlzcGxheVRleHQ+KFNpdGFyYSBldCBhbC4gMjAwNik8L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NTk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ4ZndmeHM5djJ6cnBlOWVyMmE5cHdkOWZ4djV6MnY5MndlNWQiIHRpbWVzdGFtcD0iMTUzMzAzMjE5NCI+NTk8L2tleT48a2V5IGFwcD0iRU5XZWIiIGRiLWlkPSIiPjA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNpdGFyYSwgRC48L2F1dGhvcj48YXV0aG9yPlJhenphcXVlLCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+U3QtQXJuYXVkLCBSLjwvYXV0aG9yPjxhdXRob3I+SHVhbmcsIFcuPC9hdXRob3I+PGF1dGhvcj5UYWd1Y2hpLCBULjwvYXV0aG9yPjxhdXRob3I+RXJiZW4sIFIuIEcuPC9hdXRob3I+PGF1dGhvcj5MYW5za2UsIEIuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBEZXZlbG9wbWVudGFsIEJpb2xvZ3ksIEhhcnZhcmQgU2Nob29sIG9mIERlbnRhbCBNZWRpY2luZSwgUkVCIDMwMywgMTg4IExvbmd3b29kIEF2ZS4sIEJvc3RvbiwgTUEgMDIxMTUsIFVTQSwgYW5kIFRoZSBHZW5ldGljcyBVbml0LCBTaHJpbmVycyBIb3NwaXRhbCwgTW9udHJlYWwsIFF1ZWJlYywgQ2FuYWRhLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkdlbmV0aWMgYWJsYXRpb24gb2Ygdml0YW1pbiBEIGFjdGl2YXRpb24gcGF0aHdheSByZXZlcnNlcyBiaW9jaGVtaWNhbCBhbmQgc2tlbGV0YWwgYW5vbWFsaWVzIGluIEZnZi0yMy1udWxsIGFuaW1hbHM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0gSiBQYXRob2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFBhdGhvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIxNjEtNzA8L3BhZ2VzPjx2b2x1bWU+MTY5PC92b2x1bWU+PG51bWJlcj42PC9udW1iZXI+PGVkaXRpb24+MjAwNi8xMi8wNzwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5Cb25lIERlbnNpdHkvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+Qm9uZSBhbmQgQm9uZXMvKmFibm9ybWFsaXRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+Q2FsY2lmaWNhdGlvbiwgUGh5c2lvbG9naWM8L2tleXdvcmQ+PGtleXdvcmQ+Q2FsY2l1bS9ibG9vZC91cmluZTwva2V5d29yZD48a2V5d29yZD5GaWJyb2JsYXN0IEdyb3d0aCBGYWN0b3JzLypnZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmUgRXhwcmVzc2lvbjwva2V5d29yZD48a2V5d29yZD5IaW5kbGltYi9kaWFnbm9zdGljIGltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+S2lkbmV5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBNdXRhbnQgU3RyYWluczwva2V5d29yZD48a2V5d29yZD5NaXhlZCBGdW5jdGlvbiBPeHlnZW5hc2VzL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPk1vZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3b3JkPlBhcmF0aHlyb2lkIEhvcm1vbmUvYmxvb2QvdXJpbmU8L2tleXdvcmQ+PGtleXdvcmQ+UGhvc3BoYXRlcy9ibG9vZC91cmluZTwva2V5d29yZD48a2V5d29yZD5SYWRpb2dyYXBoeTwva2V5d29yZD48a2V5d29yZD5TaWduYWwgVHJhbnNkdWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlNvZGl1bS1QaG9zcGhhdGUgQ290cmFuc3BvcnRlciBQcm90ZWlucywgVHlwZSBJSWEvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5WaXRhbWluIEQvZ2VuZXRpY3MvKm1ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkRlYzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMDItOTQ0MCAoUHJpbnQpJiN4RDswMDAyLTk0NDAgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE3MTQ4Njc4PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8xNzE0ODY3ODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUMxNzYyNDg5PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4yMzUzL2FqcGF0aC4yMDA2LjA2MDMyOTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5= ADDIN EN.

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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 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ADDIN EN.CITE 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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 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 ADDIN EN.

CITE 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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 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 ADDIN EN.

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</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. outi.

[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 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 ADDIN EN.

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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 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ADDIN EN.

CITE 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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 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ADDIN EN.CITE 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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 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ADDIN EN.CITE 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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 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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 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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 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 ADDIN EN.

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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. 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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 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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 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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 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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 <EndNote><Cite><Author>Anderson</Author><Year>2005</Year><RecNum>6</RecNum><DisplayText>[23, 26, 36]</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="r9a0z5fzo02xtzexaf6v552vztvxfwwfexdp" timestamp="1455686796">6</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. paul.anderson@imvs.sa.gov.au</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><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></keywords><dates><year>2005</year><pub-dates><date>Apr</date></pub-dates></dates><accession-num>15781002</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=15781002</url></related-urls></urls></record></Cite><Cite><Author>Chiang</Author><Year>2009</Year><RecNum>14</RecNum><record><rec-number>14</rec-number><foreign-keys><key app="EN" db-id="r9a0z5fzo02xtzexaf6v552vztvxfwwfexdp" timestamp="1455686799">14</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chiang, C.</author><author>Chiu, M.</author><author>Moore, A. J.</author><author>Anderson, P. H.</author><author>Ghasem-Zadeh, A.</author><author>McManus, J. F.</author><author>Ma, C.</author><author>Seeman, E.</author><author>Clemens, T. L.</author><author>Morris, H. A.</author><author>Zajac, J. D.</author><author>Davey, R. A.</author></authors></contributors><auth-address>Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.</auth-address><titles><title>Mineralization and bone resorption are regulated by the androgen receptor in male mice</title><secondary-title>J Bone Miner Res</secondary-title></titles><periodical><full-title>J Bone Miner Res</full-title></periodical><pages>621-31</pages><volume>24</volume><number>4</number><edition>2008/12/04</edition><keywords><keyword>Acid Phosphatase/blood</keyword><keyword>Animals</keyword><keyword>Biological Markers/blood</keyword><keyword>Bone Density/*physiology</keyword><keyword>Bone Remodeling</keyword><keyword>Bone Resorption/blood/*metabolism/pathology/*physiopathology</keyword><keyword>Femur/pathology</keyword><keyword>Gene Deletion</keyword><keyword>Integrases/metabolism</keyword><keyword>Isoenzymes/blood</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Mice, Knockout</keyword><keyword>Osteoblasts/metabolism</keyword><keyword>Osteocalcin/blood</keyword><keyword>Phenotype</keyword><keyword>Receptors, Androgen/*metabolism</keyword><keyword>Spine/metabolism/pathology</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><dates><year>2009</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1523-4681 (Electronic)&#xD;1523-4681 (Linking)</isbn><accession-num>19049333</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=19049333</url></related-urls></urls><electronic-resource-num>10.1359/jbmr.081217</electronic-resource-num><language>eng</language></record></Cite><Cite><Author>Anderson</Author><Year>2008</Year><RecNum>9</RecNum><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="r9a0z5fzo02xtzexaf6v552vztvxfwwfexdp" timestamp="1455686797">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Anderson, P. H.</author><author>Sawyer, R. K.</author><author>Moore, A. J.</author><author>May, B. K.</author><author>O&apos;Loughlin, P. D.</author><author>Morris, H. A.</author></authors></contributors><auth-address>School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia. paul.anderson@imvs.sa.gov.au</auth-address><titles><title>Vitamin D depletion induces RANKL-mediated osteoclastogenesis and bone loss in a rodent model</title><secondary-title>Journal of Bone and Mineral Research</secondary-title></titles><periodical><full-title>Journal of Bone and Mineral Research</full-title></periodical><pages>1789-97</pages><volume>23</volume><number>11</number><edition>2008/07/04</edition><keywords><keyword>25-Hydroxyvitamin D3 1-alpha-Hydroxylase/genetics/metabolism</keyword><keyword>Animals</keyword><keyword>Bone Resorption/blood/*complications/*physiopathology</keyword><keyword>Calcification, Physiologic</keyword><keyword>Disease Models, Animal</keyword><keyword>Femur/anatomy &amp; histology/enzymology</keyword><keyword>Gene Expression Regulation, Enzymologic</keyword><keyword>Male</keyword><keyword>Organ Size</keyword><keyword>*Osteogenesis</keyword><keyword>Osteomalacia/blood/complications/physiopathology</keyword><keyword>Parathyroid Hormone/blood</keyword><keyword>RANK Ligand/*metabolism</keyword><keyword>RNA, Messenger/genetics/metabolism</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword><keyword>Regression Analysis</keyword><keyword>Vitamin D/analogs &amp; derivatives/blood</keyword><keyword>Vitamin D Deficiency/blood/*complications/*physiopathology</keyword></keywords><dates><year>2008</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1523-4681 (Electronic)</isbn><accession-num>18597628</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=18597628</url></related-urls></urls><electronic-resource-num>10.1359/jbmr.080616</electronic-resource-num><language>eng</language></record></Cite></EndNote>  ADDIN EN.CITE <EndNote><Cite><Author>Anderson</Author><Year>2005</Year><RecNum>6</RecNum><DisplayText>[23, 26, 36]</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="r9a0z5fzo02xtzexaf6v552vztvxfwwfexdp" timestamp="1455686796">6</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. paul.anderson@imvs.sa.gov.au</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><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></keywords><dates><year>2005</year><pub-dates><date>Apr</date></pub-dates></dates><accession-num>15781002</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=15781002</url></related-urls></urls></record></Cite><Cite><Author>Chiang</Author><Year>2009</Year><RecNum>14</RecNum><record><rec-number>14</rec-number><foreign-keys><key app="EN" db-id="r9a0z5fzo02xtzexaf6v552vztvxfwwfexdp" timestamp="1455686799">14</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chiang, C.</author><author>Chiu, M.</author><author>Moore, A. J.</author><author>Anderson, P. H.</author><author>Ghasem-Zadeh, A.</author><author>McManus, J. F.</author><author>Ma, C.</author><author>Seeman, E.</author><author>Clemens, T. L.</author><author>Morris, H. A.</author><author>Zajac, J. D.</author><author>Davey, R. A.</author></authors></contributors><auth-address>Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.</auth-address><titles><title>Mineralization and bone resorption are regulated by the androgen receptor in male mice</title><secondary-title>J Bone Miner Res</secondary-title></titles><periodical><full-title>J Bone Miner Res</full-title></periodical><pages>621-31</pages><volume>24</volume><number>4</number><edition>2008/12/04</edition><keywords><keyword>Acid Phosphatase/blood</keyword><keyword>Animals</keyword><keyword>Biological Markers/blood</keyword><keyword>Bone Density/*physiology</keyword><keyword>Bone Remodeling</keyword><keyword>Bone Resorption/blood/*metabolism/pathology/*physiopathology</keyword><keyword>Femur/pathology</keyword><keyword>Gene Deletion</keyword><keyword>Integrases/metabolism</keyword><keyword>Isoenzymes/blood</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Mice, Knockout</keyword><keyword>Osteoblasts/metabolism</keyword><keyword>Osteocalcin/blood</keyword><keyword>Phenotype</keyword><keyword>Receptors, Androgen/*metabolism</keyword><keyword>Spine/metabolism/pathology</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><dates><year>2009</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1523-4681 (Electronic)&#xD;1523-4681 (Linking)</isbn><accession-num>19049333</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=19049333</url></related-urls></urls><electronic-resource-num>10.1359/jbmr.081217</electronic-resource-num><language>eng</language></record></Cite><Cite><Author>Anderson</Author><Year>2008</Year><RecNum>9</RecNum><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="r9a0z5fzo02xtzexaf6v552vztvxfwwfexdp" timestamp="1455686797">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Anderson, P. H.</author><author>Sawyer, R. K.</author><author>Moore, A. J.</author><author>May, B. K.</author><author>O&apos;Loughlin, P. D.</author><author>Morris, H. A.</author></authors></contributors><auth-address>School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia. paul.anderson@imvs.sa.gov.au</auth-address><titles><title>Vitamin D depletion induces RANKL-mediated osteoclastogenesis and bone loss in a rodent model</title><secondary-title>Journal of Bone and Mineral Research</secondary-title></titles><periodical><full-title>Journal of Bone and Mineral Research</full-title></periodical><pages>1789-97</pages><volume>23</volume><number>11</number><edition>2008/07/04</edition><keywords><keyword>25-Hydroxyvitamin D3 1-alpha-Hydroxylase/genetics/metabolism</keyword><keyword>Animals</keyword><keyword>Bone Resorption/blood/*complications/*physiopathology</keyword><keyword>Calcification, Physiologic</keyword><keyword>Disease Models, Animal</keyword><keyword>Femur/anatomy &amp; histology/enzymology</keyword><keyword>Gene Expression Regulation, Enzymologic</keyword><keyword>Male</keyword><keyword>Organ Size</keyword><keyword>*Osteogenesis</keyword><keyword>Osteomalacia/blood/complications/physiopathology</keyword><keyword>Parathyroid Hormone/blood</keyword><keyword>RANK Ligand/*metabolism</keyword><keyword>RNA, Messenger/genetics/metabolism</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword><keyword>Regression Analysis</keyword><keyword>Vitamin D/analogs &amp; derivatives/blood</keyword><keyword>Vitamin D Deficiency/blood/*complications/*physiopathology</keyword></keywords><dates><year>2008</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1523-4681 (Electronic)</isbn><accession-num>18597628</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=18597628</url></related-urls></urls><electronic-resource-num>10.1359/jbmr.080616</electronic-resource-num><language>eng</language></record></Cite></EndNote>  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 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ADDIN EN.CITE 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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, 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