Analysis of the Biochemical Mechanisms for the Endocrine Actions of Fibroblast Growth Factor-23

• DOI: 10.1210/en.2005-0670
• Publication Date: 2005-08-05T00:34:31Z
• Authors: Xijie Yu; Omar A. Ibrahimi; Regina Goetz; Fuming Zhang; Siobhan I. Davis; Holly J. Garringer; Robert J. Linhardt; David M. Ornitz; Moosa Mohammadi; Kenneth E. White
• Keywords: Hypophosphatemia; Enteroendocrine cell

Fibroblast growth factor (FGF)-23 has emerged as an endocrine regulator of phosphate and vitamin D metabolism. It is produced in bone and, unlike other FGFs, circulates the bloodstream to ultimately regulate handling production kidney. Presently, it unknown which seven principal FGF receptors (FGFRs) transmits FGF23 biological activity. Furthermore, molecular basis for mode action unclear. Herein, we performed surface plasmon resonance mitogenesis experiments comprehensively characterize receptor binding specificity. Our data demonstrate that binds activates c splice isoforms FGFR1–3, well FGFR4, but not b FGFR1–3. Interestingly, highly sulfated longer glycosaminoglycan (GAG) species were capable promoting mitogenic We also show induces tyrosine phosphorylation inhibits sodium-phosphate cotransporter Npt2a mRNA expression using opossum kidney cells, a model proximal tubule cell line. Removal GAGs abolishes effects FGF23, exogenous GAG restoring activity, suggesting cells naturally express are permissive action. propose signals through multiple FGFRs unique actions involve escape from FGF23-producing circulation kidney, where most likely act cofactors biochemical findings provide important insights into mechanisms by dysregulated signaling leads disorders hyper- hypophosphatemia.