{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:41:57Z","timestamp":1791276117505,"version":"4.1.0"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2008,9,1]],"date-time":"2008-09-01T00:00:00Z","timestamp":1220227200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Fibroblast growth factor (FGF)23 is proposed to play a physiological role in the regulation of phosphate and vitamin D metabolism; deranged circulatory levels of FGF23 cause several diseases with abnormal mineral metabolism. This paper presents a novel approach to analyze the mechanism of action of FGF23 using anti-FGF23 monoclonal antibodies that can neutralize FGF23 activities both in vitro and in vivo. We developed two antibodies (FN1 and FC1) that recognize the N- and C-terminal regions of FGF23, respectively. Both FN1 and FC1 inhibited FGF23 activity in a cell-based Klotho-dependent reporter assay. Their administration caused marked increases in serum phosphate and 1,25D levels in normal mice. These changes were accompanied by altered expression in the kidney of type IIa sodium-phosphate cotransporter, 25-hydroxyvitamin-D-1\u03b1-hydroxylase, and 24-hydroxylase. Thus, this study using neutralizing antibodies confirms that FGF23 is a physiological regulator of phosphate and vitamin D metabolism. We addressed the mechanism of action for these neutralizing antibodies. Structural analysis of the FGF23\/FN1-Fab complex showed that FN1 masked putative FGF receptor-binding sites in the N-terminal domain of FGF23, whereas biochemical analyses showed that FC1 interfered with the association between FGF23 and Klotho by binding to the C-terminal domain of FGF23. Taken together, our results suggest that the N- and C-terminal domains of FGF23 are responsible for association with cognate FGF receptors and Klotho, respectively, and that these interactions are indispensable for FGF23 activity.<\/jats:p>","DOI":"10.1359\/jbmr.080417","type":"journal-article","created":{"date-parts":[[2008,4,28]],"date-time":"2008-04-28T15:27:26Z","timestamp":1209396446000},"page":"1509-1518","source":"Crossref","is-referenced-by-count":177,"title":["Anti-FGF23 Neutralizing Antibodies Show the Physiological Role and Structural Features of FGF23"],"prefix":"10.1093","volume":"23","author":[{"given":"Yuji","family":"Yamazaki","sequence":"first","affiliation":[{"name":"These authors contributed equally to this work"},{"name":"Discovery Research Laboratories, Kirin Pharma, Gunma, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taro","family":"Tamada","sequence":"additional","affiliation":[{"name":"Quantum Beam Science Directorate, Japan Atomic Energy Agency, Ibaraki, Japan"},{"name":"These authors contributed equally to this work"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriyuki","family":"Kasai","sequence":"additional","affiliation":[{"name":"Development Research Laboratories, Kirin Pharma, Gunma, Japan"},{"name":"These authors contributed equally to this work"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itaru","family":"Urakawa","sequence":"additional","affiliation":[{"name":"Discovery Research Laboratories, Kirin Pharma, Gunma, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiko","family":"Aono","sequence":"additional","affiliation":[{"name":"Discovery Research Laboratories, Kirin Pharma, Gunma, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisashi","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Discovery Research Laboratories, Kirin Pharma, Gunma, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiro","family":"Fujita","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Endocrinology, Department of Medicine, The University of Tokyo Hospital, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryota","family":"Kuroki","sequence":"additional","affiliation":[{"name":"Quantum Beam Science Directorate, Japan Atomic Energy Agency, Ibaraki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeyoshi","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Discovery Research Laboratories, Kirin Pharma, Gunma, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiji","family":"Fukumoto","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Endocrinology, Department of Medicine, The University of Tokyo Hospital, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Shimada","sequence":"additional","affiliation":[{"name":"Discovery Research Laboratories, Kirin Pharma, Gunma, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,12,4]]},"reference":[{"key":"2024020319500398900_bib1","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/81664","article-title":"Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23","volume":"26","author":"The ADHR Consortium","year":"2000","journal-title":"Nat Genet"},{"key":"2024020319500398900_bib2","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1359\/jbmr.070107","article-title":"FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets","volume":"22","author":"Imel","year":"2007","journal-title":"J Bone Miner Res"},{"key":"2024020319500398900_bib3","doi-asserted-by":"crossref","first-page":"6500","DOI":"10.1073\/pnas.101545198","article-title":"Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia","volume":"98","author":"Shimada","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024020319500398900_bib4","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1210\/jcem.86.2.7408","article-title":"The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting","volume":"86","author":"White","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"2024020319500398900_bib5","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"},{"key":"2024020319500398900_bib6","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"},{"key":"2024020319500398900_bib7","doi-asserted-by":"crossref","first-page":"5523","DOI":"10.1210\/jc.2005-0301","article-title":"A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis","volume":"90","author":"Araya","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"2024020319500398900_bib8","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.1210\/jc.2004-2238","article-title":"A novel recessive mutation in fibroblast growth factor-23 causes familial tumoral calcinosis","volume":"90","author":"Larsson","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"2024020319500398900_bib9","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1172\/JCI200419081","article-title":"Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism","volume":"113","author":"Shimada","year":"2004","journal-title":"J Clin Invest"},{"key":"2024020319500398900_bib10","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"},{"key":"2024020319500398900_bib11","doi-asserted-by":"crossref","first-page":"4957","DOI":"10.1210\/jc.2002-021105","article-title":"Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets\/osteomalacia","volume":"87","author":"Yamazaki","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2024020319500398900_bib12","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1359\/jbmr.061105","article-title":"Hyperostosis-hyperphosphatemia syndrome: A congenital disorder of O-glycosylation associated with augmented processing of fibroblast growth factor 23","volume":"22","author":"Frishberg","year":"2007","journal-title":"J Bone Miner Res"},{"key":"2024020319500398900_bib13","doi-asserted-by":"crossref","first-page":"593","DOI":"10.4049\/jimmunol.102.3.593","article-title":"A glycoprotein that induces nephrotoxic antibody: Its isolation and purification from rat glomerular basement membrane","volume":"102","author":"Shibata","year":"1969","journal-title":"J Immunol"},{"key":"2024020319500398900_bib14","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"},{"key":"2024020319500398900_bib15","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"},{"key":"2024020319500398900_bib16","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"},{"key":"2024020319500398900_bib17","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0076-6879(97)76066-X","article-title":"Processing of X-ray diffraction data collected in oscillation mode","volume":"276","author":"Otwinoski","year":"1997","journal-title":"Methods Enzymol"},{"key":"2024020319500398900_bib18","first-page":"432","article-title":"Likelihood-enhanced fast rotation functions","volume":"D60","author":"Storoni","year":"2004","journal-title":"Acta Crystallogr"},{"key":"2024020319500398900_bib19","first-page":"905","article-title":"Crystallography and NMR system (CNS): A new software system for macromolecular structure determination","volume":"D54","author":"Br\u00fcnger","year":"1998","journal-title":"Acta Crystallogr"},{"key":"2024020319500398900_bib20","first-page":"240","article-title":"Refinement of macromolecular structures by the maximum-likelihood method","volume":"D53","author":"Murshudov","year":"1997","journal-title":"Acta Crystallogr"},{"key":"2024020319500398900_bib21","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.bone.2004.04.002","article-title":"FGF23 is processed by proprotein convertases but not by PHEX","volume":"35","author":"Benet-Pages","year":"2004","journal-title":"Bone"},{"key":"2024020319500398900_bib22","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"},{"key":"2024020319500398900_bib23","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"},{"key":"2024020319500398900_bib24","doi-asserted-by":"crossref","first-page":"5358","DOI":"10.1210\/en.2005-0777","article-title":"Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice","volume":"146","author":"Perwad","year":"2005","journal-title":"Endocrinology"},{"key":"2024020319500398900_bib25","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/sj.ki.5000020","article-title":"Effect of manipulating serum phosphorus with phosphate binder on circulating PTH and FGF23 in renal failure rats","volume":"69","author":"Nagano","year":"2006","journal-title":"Kidney Int"},{"key":"2024020319500398900_bib26","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1073\/pnas.91.3.900","article-title":"Identification of a vitamin D-response element in the rat calcidiol (25-hydroxyvitamin D3) 24-hydroxylase gene","volume":"91","author":"Zierold","year":"1994","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024020319500398900_bib27","first-page":"4003","article-title":"The parathyroid is a target organ for FGF23 in rats","volume":"117","author":"Ben-Dov","year":"2007","journal-title":"J Clin Invest"},{"key":"2024020319500398900_bib28","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1677\/JOE-07-0267","article-title":"Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells","volume":"195","author":"Krajisnik","year":"2007","journal-title":"J Endocrinol"},{"key":"2024020319500398900_bib29","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"},{"key":"2024020319500398900_bib30","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1021\/bi035320k","article-title":"The crystal structure of fibroblast growth factor (FGF) 19 reveals novel features of the FGF family and offers a structural basis for its unusual receptor affinity","volume":"43","author":"Harmer","year":"2004","journal-title":"Biochemistry"},{"key":"2024020319500398900_bib31","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/S0092-8674(00)80851-X","article-title":"Crystal structures of two FGF-FGFR complexes reveal the determinants of ligand-receptor specificity","volume":"101","author":"Plotnikov","year":"2000","journal-title":"Cell"},{"key":"2024020319500398900_bib32","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/S0092-8674(00)80051-3","article-title":"Structural basis for FGF receptor dimerization and activation","volume":"98","author":"Plotnikov","year":"1999","journal-title":"Cell"},{"key":"2024020319500398900_bib33","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/S1097-2765(00)00073-3","article-title":"Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization","volume":"6","author":"Schlessinger","year":"2000","journal-title":"Mol Cell"},{"key":"2024020319500398900_bib34","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.matbio.2006.10.003","article-title":"Ablation of vitamin D signaling rescues bone, mineral, and glucose homeostasis in Fgf-23 deficient mice","volume":"26","author":"Hesse","year":"2007","journal-title":"Matrix Biol"},{"key":"2024020319500398900_bib35","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1096\/fj.05-5432fje","article-title":"Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process","volume":"20","author":"Razzaque","year":"2006","journal-title":"FASEB J"},{"key":"2024020319500398900_bib36","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1042\/BJ20041799","article-title":"Role of the vitamin D receptor in FGF23 action on phosphate metabolism","volume":"390","author":"Inoue","year":"2005","journal-title":"Biochem J"},{"key":"2024020319500398900_bib37","doi-asserted-by":"crossref","first-page":"F1088","DOI":"10.1152\/ajprenal.00474.2004","article-title":"Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism","volume":"289","author":"Shimada","year":"2005","journal-title":"Am J Physiol Renal Physiol"},{"key":"2024020319500398900_bib38","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"},{"key":"2024020319500398900_bib39","doi-asserted-by":"crossref","first-page":"4647","DOI":"10.1210\/en.2005-0670","article-title":"Analysis of the biochemical mechanisms for the endocrine actions of fibroblast growth factor-23","volume":"146","author":"Yu","year":"2005","journal-title":"Endocrinology"},{"key":"2024020319500398900_bib40","doi-asserted-by":"crossref","first-page":"2393","DOI":"10.1210\/me.2003-0048","article-title":"Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system","volume":"17","author":"Tsujikawa","year":"2003","journal-title":"Mol Endocrinol"},{"key":"2024020319500398900_bib41","doi-asserted-by":"crossref","first-page":"2684","DOI":"10.1172\/JCI31330","article-title":"A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis","volume":"117","author":"Ichikawa","year":"2007","journal-title":"J Clin Invest"},{"key":"2024020319500398900_bib42","first-page":"40A","article-title":"FGF-23 plays a critical role in the development of reduced serum 1,25-dihydroxyvitamin D (1,25D) levels associated with renal insufficiency","volume":"14","author":"Hasegawa","year":"2003","journal-title":"J Am Soc Nephrol"},{"key":"2024020319500398900_bib43","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1097\/MNH.0b013e3281ca6ffd","article-title":"Emerging role of fibroblast growth factor 23 in a bone-kidney axis regulating systemic phosphate homeostasis and extracellular matrix mineralization","volume":"16","author":"Liu","year":"2007","journal-title":"Curr Opin Nephrol Hypertens"},{"key":"2024020319500398900_bib44","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1053\/j.ajkd.2004.04.029","article-title":"Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency","volume":"44","author":"Shigematsu","year":"2004","journal-title":"Am J Kidney Dis"},{"key":"2024020319500398900_bib45","doi-asserted-by":"crossref","first-page":"3367","DOI":"10.1093\/nar\/gkg581","article-title":"MATRAS: A program for protein 3D structure comparison","volume":"31","author":"Kawabata","year":"2003","journal-title":"Nucleic Acids Res"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1359%2Fjbmr.080417","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/23\/9\/1509\/56571169\/5650230918.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/23\/9\/1509\/56571169\/5650230918.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T10:50:57Z","timestamp":1710327057000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/23\/9\/1509-1518\/7599550"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,9,1]]},"references-count":45,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2009,12,4]]},"published-print":{"date-parts":[[2008,9,1]]}},"URL":"https:\/\/doi.org\/10.1359\/jbmr.080417","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1108378.564418","asserted-by":"object"}]},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2008,9,1]]},"published":{"date-parts":[[2008,9,1]]}}}