title: Circulating αKlotho influences phosphate handling by controlling FGF23 production.
abstract: The FGF23 coreceptor αKlotho (αKL) is expressed as a membrane-bound protein (mKL) that forms heteromeric complexes with FGF receptors (FGFRs) to initiate intracellular signaling. It also circulates as an endoproteolytic cleavage product of mKL (cKL). Previously, a patient with increased plasma cKL as the result of a translocation [t(9;13)] in the αKLOTHO (KL) gene presented with rickets and a complex endocrine profile, including paradoxically elevated plasma FGF23, despite hypophosphatemia. The goal of this study was to test whether cKL regulates phosphate handling through control of FGF23 expression. To increase cKL levels, mice were treated with an adeno-associated virus producing cKL. The treated groups exhibited dose-dependent hypophosphatemia and hypocalcemia, with markedly elevated FGF23 (38 to 456 fold). The animals also manifested fractures, reduced bone mineral content, expanded growth plates, and severe osteomalacia, with highly increased bone Fgf23 mRNA (>150 fold). cKL activity in vitro was specific for interactions with FGF23 and was FGFR dependent. These results demonstrate that cKL potently stimulates FGF23 production in vivo, which phenocopies the KL translocation patient and metabolic bone syndromes associated with elevated FGF23. These findings have important implications for the regulation of αKL and FGF23 in disorders of phosphate handling and biomineralization.
authors.affiliation: Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: Rosamund C
authors.initials: RC
authors.lastname: Smith
authors.forename: Linda M
authors.initials: LM
authors.lastname: O'Bryan
authors.forename: Emily G
authors.initials: EG
authors.lastname: Farrow
authors.forename: Lelia J
authors.initials: LJ
authors.lastname: Summers
authors.forename: Erica L
authors.initials: EL
authors.lastname: Clinkenbeard
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Roberts
authors.forename: Taryn A
authors.initials: TA
authors.lastname: Cass
authors.forename: Joy
authors.initials: J
authors.lastname: Saha
authors.forename: Carol
authors.initials: C
authors.lastname: Broderick
authors.forename: Y Linda
authors.initials: YL
authors.lastname: Ma
authors.forename: Qing Qiang
authors.initials: QQ
authors.lastname: Zeng
authors.forename: Alexei
authors.initials: A
authors.lastname: Kharitonenkov
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Wilson
authors.forename: Qianxu
authors.initials: Q
authors.lastname: Guo
authors.forename: Haijun
authors.initials: H
authors.lastname: Sun
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Allen
authors.forename: David B
authors.initials: DB
authors.lastname: Burr
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Breyer
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: White
mesh_terms: D000818:Animals; D015519:Bone Density; D001842:Bone and Bones / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005966:Glucuronidase; D007668:Kidney / Q000378:metabolism; D000090265:Klotho Proteins; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D009928:Organ Specificity; D010641:Phenotype; D010710:Phosphates / Q000097:blood*; D011859:Radiography; D011956:Receptors, Cell Surface / Q000097:blood* / Q000235:genetics
chemical_list: C000717428:Fgf23 protein, mouse; D010710:Phosphates; D011956:Receptors, Cell Surface; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins