title: Antibody-mediated activation of FGFR1 induces FGF23 production and hypophosphatemia.
abstract: The phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) controls phosphate homeostasis by regulating renal expression of sodium-dependent phosphate co-transporters and cytochrome P450 enzymes involved in vitamin D catabolism. Multiple FGF Receptors (FGFRs) can act as receptors for FGF23 when bound by the co-receptor Klotho expressed in the renal tubular epithelium. FGFRs also regulate skeletal FGF23 secretion; ectopic FGFR activation is implicated in genetic conditions associated with FGF23 overproduction and hypophosphatemia. The identity of FGFRs that mediate the activity of FGF23 or that regulate skeletal FGF23 secretion remains ill defined. Here we report that pharmacological activation of FGFR1 with monoclonal anti-FGFR1 antibodies (R1MAb) in adult mice is sufficient to cause an elevation in serum FGF23 and mild hypophosphatemia. In cultured rat calvariae osteoblasts, R1MAb induces FGF23 mRNA expression and FGF23 protein secretion into the culture medium. In a cultured kidney epithelial cell line, R1MAb acts as a functional FGF23 mimetic and activates the FGF23 program. siRNA-mediated Fgfr1 knockdown induced the opposite effects. Taken together, our work reveals the central role of FGFR1 in the regulation of FGF23 production and signal transduction, and has implications in the pathogenesis of FGF23-related hypophosphatemic disorders.
authors: Department of Molecular Biology, Genentech, Inc., South San Francisco, California, United States of America.
authors: Ai-Luen
authors: AL
authors: Wu
authors: Bo
authors: B
authors: Feng
authors: Mark Z
authors: MZ
authors: Chen
authors: Ganesh
authors: G
authors: Kolumam
authors: Jose
authors: J
authors: Zavala-Solorio
authors: Shelby K
authors: SK
authors: Wyatt
authors: Vineela D
authors: VD
authors: Gandham
authors: Richard A D
authors: RA
authors: Carano
authors: Junichiro
authors: J
authors: Sonoda
mesh_terms: D000818:Animals; D001483:Base Sequence; D015519:Bone Density; D002478:Cells, Cultured; D017931:DNA Primers; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000096:biosynthesis*; D017674:Hypophosphatemia / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000276:immunology*
chemical_list: D017931:DNA Primers; C000717428:Fgf23 protein, mouse; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D051496:Receptor, Fibroblast Growth Factor, Type 1