{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T01:16:51Z","timestamp":1793755011778,"version":"4.6.1"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2017,6,10]],"date-time":"2017-06-10T00:00:00Z","timestamp":1497052800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Carol Fritz and other Biomarker team members for serum and urine chemistry analyses"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,10,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>\u2003<\/jats:title>\n                    <jats:p>Fibroblast growth factor 23 (FGF23) is the causative factor of X-linked hypophosphatemia (XLH), a genetic disorder effecting 1:20,000 that is characterized by excessive phosphate excretion, elevated FGF23 levels and a rickets\/osteomalacia phenotype. FGF23 inhibits phosphate reabsorption and suppresses 1\u03b1,25-dihydroxyvitamin D (1,25D) biosynthesis, analytes that differentially contribute to bone integrity and deleterious soft-tissue mineralization. As inhibition of ligand broadly modulates downstream targets, balancing efficacy and unwanted toxicity is difficult when targeting the FGF23 pathway. We demonstrate that a FGF23 c-tail-Fc fusion molecule selectively modulates the phosphate pathway in vivo by competitive antagonism of FGF23 binding to the FGFR\/\u03b1 klotho receptor complex. Repeated injection of FGF23 c-tail Fc in Hyp mice, a preclinical model of XLH, increases cell surface abundance of kidney NaPi transporters, normalizes phosphate excretion, and significantly improves bone architecture in the absence of soft-tissue mineralization. Repeated injection does not modulate either 1,25D or calcium in a physiologically relevant manner in either a wild-type or disease setting. These data suggest that bone integrity can be improved in models of XLH via the exclusive modulation of phosphate. We posit that the selective modulation of the phosphate pathway will increase the window between efficacy and safety risks, allowing increased efficacy to be achieved in the treatment of this chronic disease. \u00a9 2017 American Society for Bone and Mineral Research.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jbmr.3197","type":"journal-article","created":{"date-parts":[[2017,6,10]],"date-time":"2017-06-10T08:22:42Z","timestamp":1497082962000},"page":"2062-2073","source":"Crossref","is-referenced-by-count":34,"title":["Therapeutic Effects of FGF23 c-tail Fc in a Murine Preclinical Model of X-Linked Hypophosphatemia Via the Selective Modulation of Phosphate Reabsorption"],"prefix":"10.1093","volume":"32","author":[{"given":"Kristen","family":"Johnson","sequence":"first","affiliation":[{"name":"Center for Therapeutic InnovationPfizerNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kymberly","family":"Levine","sequence":"additional","affiliation":[{"name":"Center for Therapeutic InnovationPfizerNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Sergi","sequence":"additional","affiliation":[{"name":"Center for Therapeutic InnovationPfizerNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Chamoun","sequence":"additional","affiliation":[{"name":"Center for Therapeutic InnovationPfizerNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Roach","sequence":"additional","affiliation":[{"name":"Center for Therapeutic InnovationPfizerNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Vekich","sequence":"additional","affiliation":[{"name":"Center for Therapeutic InnovationPfizerNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"Favis","sequence":"additional","affiliation":[{"name":"Center for Therapeutic InnovationPfizerNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Horn","sequence":"additional","affiliation":[{"name":"Center for Therapeutic InnovationPfizerNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianjun","family":"Cao","sequence":"additional","affiliation":[{"name":"Center for Therapeutic InnovationPfizerNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Miller","sequence":"additional","affiliation":[{"name":"Center for Therapeutic InnovationPfizerNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Snyder","sequence":"additional","affiliation":[{"name":"Center for Therapeutic InnovationPfizerNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dikran","family":"Aivazian","sequence":"additional","affiliation":[{"name":"Center for Therapeutic InnovationPfizerNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Reagan","sequence":"additional","affiliation":[{"name":"Drug Safety Research and DevelopmentPfizerGrotonCTUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin","family":"Berryman","sequence":"additional","affiliation":[{"name":"Comparative MedicinePfizerGrotonCTUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Colangelo","sequence":"additional","affiliation":[{"name":"Drug Safety Research and DevelopmentPfizerGrotonCTUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Markiewicz","sequence":"additional","affiliation":[{"name":"Drug Safety Research and DevelopmentPfizerGrotonCTUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cedo M","family":"Bagi","sequence":"additional","affiliation":[{"name":"Comparative MedicinePfizerGrotonCTUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas P","family":"Brown","sequence":"additional","affiliation":[{"name":"Drug Safety Research and DevelopmentPfizerGrotonCTUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Coyle","sequence":"additional","affiliation":[{"name":"Center for Therapeutic InnovationPfizerNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moosa","family":"Mohammadi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular PharmacologyNew York University School of MedicineNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne","family":"Magram","sequence":"additional","affiliation":[{"name":"Center for Therapeutic InnovationPfizerNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,6,10]]},"reference":[{"issue":"7","key":"2024021014201575500_jbmr3197-bib-0001","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1002\/jbmr.340","article-title":"A clinician's guide to X-linked hypophosphatemia","volume":"26","author":"Carpenter","year":"2011","journal-title":"J Bone Miner Res"},{"key":"2024021014201575500_jbmr3197-bib-0002","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1146\/annurev.med.051308.111339","article-title":"Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23","volume":"61","author":"Bergwitz","year":"2010","journal-title":"Annu Rev Med"},{"issue":"2","key":"2024021014201575500_jbmr3197-bib-0003","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.bbrc.2003.12.102","article-title":"FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa","volume":"314","author":"Shimada","year":"2004","journal-title":"Biochem Biophys Res Commun"},{"issue":"2","key":"2024021014201575500_jbmr3197-bib-0004","doi-asserted-by":"crossref","first-page":"F282","DOI":"10.1152\/ajprenal.90742.2008","article-title":"FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1","volume":"297","author":"Gattineni","year":"2009","journal-title":"Am J Physiol Renal Physiol"},{"issue":"7","key":"2024021014201575500_jbmr3197-bib-0005","doi-asserted-by":"crossref","first-page":"3087","DOI":"10.1210\/en.2003-1768","article-title":"Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis","volume":"145","author":"Larsson","year":"2004","journal-title":"Endocrinology"},{"issue":"11","key":"2024021014201575500_jbmr3197-bib-0006","doi-asserted-by":"crossref","first-page":"9843","DOI":"10.1074\/jbc.M210490200","article-title":"The autosomal dominant hypophosphatemic rickets R176Q mutation in fibroblast growth factor 23 resists proteolytic cleavage and enhances in vivo biological potency","volume":"278","author":"Bai","year":"2003","journal-title":"J Biol Chem"},{"issue":"11","key":"2024021014201575500_jbmr3197-bib-0007","doi-asserted-by":"crossref","first-page":"5269","DOI":"10.1210\/en.2004-0233","article-title":"Transgenic mice overexpressing human fibroblast growth factor 23 (R176Q) delineate a putative role for parathyroid hormone in renal phosphate wasting disorders","volume":"145","author":"Bai","year":"2004","journal-title":"Endocrinology"},{"issue":"3","key":"2024021014201575500_jbmr3197-bib-0008","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1359\/JBMR.0301264","article-title":"FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis","volume":"19","author":"Shimada","year":"2004","journal-title":"J Bone Miner Res"},{"issue":"8","key":"2024021014201575500_jbmr3197-bib-0009","doi-asserted-by":"crossref","first-page":"3179","DOI":"10.1210\/endo.143.8.8795","article-title":"Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo","volume":"143","author":"Shimada","year":"2002","journal-title":"Endocrinology"},{"issue":"6","key":"2024021014201575500_jbmr3197-bib-0010","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1046\/j.1523-1755.2001.00064.x","article-title":"Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23","volume":"60","author":"White","year":"2001","journal-title":"Kidney Int"},{"issue":"9","key":"2024021014201575500_jbmr3197-bib-0011","doi-asserted-by":"crossref","first-page":"3417","DOI":"10.1128\/MCB.02249-06","article-title":"Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members","volume":"27","author":"Goetz","year":"2007","journal-title":"Mol Cell Biol"},{"issue":"1","key":"2024021014201575500_jbmr3197-bib-0012","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1073\/pnas.0902006107","article-title":"Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation","volume":"107","author":"Goetz","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"2024021014201575500_jbmr3197-bib-0013","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1210\/en.2011-1831","article-title":"Chronic inhibition of ERK1\/2 signaling improves disordered bone and mineral metabolism in hypophosphatemic (Hyp) mice","volume":"153","author":"Zhang","year":"2012","journal-title":"Endocrinology"},{"issue":"34","key":"2024021014201575500_jbmr3197-bib-0014","doi-asserted-by":"crossref","first-page":"29134","DOI":"10.1074\/jbc.M112.342980","article-title":"Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor","volume":"287","author":"Goetz","year":"2012","journal-title":"J Biol Chem"},{"issue":"7","key":"2024021014201575500_jbmr3197-bib-0015","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.matbio.2004.09.007","article-title":"Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice","volume":"23","author":"Sitara","year":"2004","journal-title":"Matrix Biol"},{"issue":"1","key":"2024021014201575500_jbmr3197-bib-0016","doi-asserted-by":"crossref","first-page":"E38","DOI":"10.1152\/ajpendo.00008.2006","article-title":"Pathogenic role of Fgf23 in Hyp mice","volume":"291","author":"Liu","year":"2006","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"11","key":"2024021014201575500_jbmr3197-bib-0017","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1359\/jbmr.090509","article-title":"Therapeutic effects of anti-FGF23 antibodies in hypophosphatemic rickets\/osteomalacia","volume":"24","author":"Aono","year":"2009","journal-title":"J Bone Miner Res"},{"issue":"9","key":"2024021014201575500_jbmr3197-bib-0018","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1359\/jbmr.080417","article-title":"Anti-FGF23 neutralizing antibodies show the physiological role and structural features of FGF23","volume":"23","author":"Yamazaki","year":"2008","journal-title":"J Bone Miner Res"},{"issue":"12","key":"2024021014201575500_jbmr3197-bib-0019","doi-asserted-by":"crossref","first-page":"4667","DOI":"10.1073\/pnas.73.12.4667","article-title":"Hypophosphatemia: mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets","volume":"73","author":"Eicher","year":"1976","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"2024021014201575500_jbmr3197-bib-0020","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1210\/endo-107-5-1577","article-title":"Abnormal vitamin D metabolism in the X-linked hypophosphatemic mouse","volume":"107","author":"Meyer","year":"1980","journal-title":"Endocrinology"},{"issue":"2","key":"2024021014201575500_jbmr3197-bib-0021","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/BF02409431","article-title":"Serum 1,25-dihydroxyvitamin D concentration in hypophosphatemic vitamin D-resistant rickets","volume":"33","author":"Delvin","year":"1981","journal-title":"Calcif Tissue Int"},{"issue":"4","key":"2024021014201575500_jbmr3197-bib-0022","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1002\/jbmr.1810","article-title":"Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets","volume":"28","author":"Wohrle","year":"2013","journal-title":"J Bone Miner Res"},{"issue":"3","key":"2024021014201575500_jbmr3197-bib-0023","doi-asserted-by":"crossref","first-page":"E508","DOI":"10.1152\/ajpendo.00499.2010","article-title":"Compound deletion of Fgfr3 and Fgfr4 partially rescues the Hyp mouse phenotype","volume":"300","author":"Li","year":"2011","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"2","key":"2024021014201575500_jbmr3197-bib-0024","doi-asserted-by":"crossref","first-page":"F371","DOI":"10.1152\/ajprenal.00740.2010","article-title":"Regulation of serum 1,25(OH)2 vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4","volume":"301","author":"Gattineni","year":"2011","journal-title":"Am J Physiol Renal Physiol"},{"issue":"10","key":"2024021014201575500_jbmr3197-bib-0025","doi-asserted-by":"crossref","first-page":"6120","DOI":"10.1074\/jbc.C500457200","article-title":"Regulation of fibroblast growth factor-23 signaling by klotho","volume":"281","author":"Kurosu","year":"2006","journal-title":"J Biol Chem"},{"issue":"7120","key":"2024021014201575500_jbmr3197-bib-0026","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/nature05315","article-title":"Klotho converts canonical FGF receptor into a specific receptor for FGF23","volume":"444","author":"Urakawa","year":"2006","journal-title":"Nature"},{"issue":"6","key":"2024021014201575500_jbmr3197-bib-0027","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.2353\/ajpath.2006.060329","article-title":"Genetic ablation of vitamin D activation pathway reverses biochemical and skeletal anomalies in Fgf-23-null animals","volume":"169","author":"Sitara","year":"2006","journal-title":"Am J Pathol"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbmr.3197","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/32\/10\/2062\/56651820\/jbmr3197.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/32\/10\/2062\/56651820\/jbmr3197.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T10:59:17Z","timestamp":1710327557000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/32\/10\/2062-2073\/7605500"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6,10]]},"references-count":27,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2017,6,10]]},"published-print":{"date-parts":[[2017,10,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.3197","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2017,10,1]]},"published":{"date-parts":[[2017,6,10]]}}}