Fibroblast growth factor 23 (FGF23): From synthesis to cleavage

Fibroblast growth factor 23 (FGF23) maintains phosphate and vitamin D homeostasis. In the kidney, recognition of FGF23 is mediated by fibroblast growth factor receptors (FGFRs), α-Klotho, and heparan sulfate. Structural studies indicate that an FGF23-FGFR-α-Klotho recognition unit recruits a second FGFR with assistance from heparan sulfate to form an asymmetric 1:2:1:1 complex that activates Ras-mitogen-activated protein kinase (MAPK) signaling. Circulating intact FGF23 reflects transcription, post-translational processing, secretion, and clearance. In FGF23-producing cells, polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3)-mediated O-glycosylation at Thr178 protects the cleavage site, whereas phosphorylation of Ser180 by FAM20C, a Golgi-associated secretory pathway kinase, limits this protection. Furin and related proprotein convertases cleave FGF23 within the secretory pathway, although their in vivo contributions remain unresolved. In cell-free experiments, tissue-type and urokinase-type plasminogen activators directly cleave recombinant FGF23; mouse data also implicate the plasminogen activator inhibitor-1 axis, but its quantitative contribution to the human circulating pool is unknown. Receptor availability further shapes signaling. Although osteocytes and osteoblasts are the principal endocrine sources, human skin cells express and secrete FGF23 in vitro. Their response to 1,25-dihydroxyvitamin D₃ depends partly on the vitamin D receptor, but whether skin contributes to circulating FGF23 remains undefined. Chronic kidney disease, autosomal dominant hypophosphatemic rickets, hyperphosphatemic familial tumoral calcinosis, X-linked hypophosphatemia, Raine syndrome, and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) deficiency illustrate the relationships among FGF23 processing, bone-matrix signaling, and pyrophosphate homeostasis. This review integrates these mechanisms and evaluates burosumab, selective FGFR inhibition, C-terminal peptides, small-molecule antagonists, and ENPP1 enzyme replacement according to current evidence.