Analysis of the biochemical mechanisms for the endocrine actions of fibroblast growth factor-23.
Fibroblast growth factor (FGF)-23 has emerged as an endocrine regulator of phosphate and of vitamin D metabolism. It is produced in bone and, unlike other FGFs, circulates in the bloodstream to ultimately regulate phosphate handling and vitamin D production in the kidney. Presently, it is unknown which of the seven principal FGF receptors (FGFRs) transmits FGF23 biological activity. Furthermore, the molecular basis for the endocrine mode of FGF23 action is unclear. Herein, we performed surface plasmon resonance and mitogenesis experiments to comprehensively characterize receptor binding specificity. Our data demonstrate that FGF23 binds and activates the c splice isoforms of FGFR1-3, as well as FGFR4, but not the b splice isoforms of FGFR1-3. Interestingly, highly sulfated and longer glycosaminoglycan (GAG) species were capable of promoting FGF23 mitogenic activity. We also show that FGF23 induces tyrosine phosphorylation and inhibits sodium-phosphate cotransporter Npt2a mRNA expression using opossum kidney cells, a model kidney proximal tubule cell line. Removal of cell surface GAGs abolishes the effects of FGF23, and exogenous highly sulfated GAG is capable of restoring FGF23 activity, suggesting that proximal tubule cells naturally express GAGs that are permissive for FGF23 action. We propose that FGF23 signals through multiple FGFRs and that the unique endocrine actions of FGF23 involve escape from FGF23-producing cells and circulation to the kidney, where highly sulfated GAGs most likely act as cofactors for FGF23 activity. Our biochemical findings provide important insights into the molecular mechanisms by which dysregulated FGF23 signaling leads to disorders of hyper- and hypophosphatemia.
Yu
Xijie
X
Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Ibrahimi
Omar A
OA
Goetz
Regina
R
Zhang
Fuming
F
Davis
Siobhan I
SI
Garringer
Holly J
HJ
Linhardt
Robert J
RJ
Ornitz
David M
DM
Mohammadi
Moosa
M
White
Kenneth E
KE
D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D004703:Endocrine System / Q000502:physiology*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D006025:Glycosaminoglycans / Q000378:metabolism; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D011108:Polymers / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
C000717427:FGF23 protein, human; D006025:Glycosaminoglycans; D011108:Polymers; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; C013786:A73025; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D006493:Heparin; D011505:Protein-Tyrosine Kinases