Fibroblast growth factor 23 (FGF23) is a single-chain protein with 251 amino acids, including a 24-amino-acid leader sequence. It inhibits 1,25(OH)2D production and phosphate reabsorption (via the sodium phosphate co-transporters NaPi 2a and 2c) in the kidney and can lead to both hypophosphatemia and inappropriately low levels of circulating 1,25(OH)2D. Whereas FGF23 was originally identified in certain mesenchymal tumors, osteoblasts and osteocytes in bone appear to be its primary site of production. Other tissues can also produce FGF23, though at lower levels. FGF23 requires O-glycosylation for its secretion, a glycosylation mediated by the glycosyl transferase GALNT3. Mutations in GALNT3 result in abnormal deposition of calcium phosphate in periarticular tissues (tumoral calcinosis) with elevated phosphate and 1,25(OH)2D. FGF23 is normally inactivated by cleavage at an RXXR site (amino acids 176–179). Mutations in this site lead to excess FGF23, the underlying problem in autosomal dominant hypophosphatemic rickets. A similar disease, X-linked hypophosphatemic rickets, is due to mutations in PHEX, an endopeptidase, which initially was thought to cleave FGF23. However, this concept has been shown to be invalid, and the mechanism by which PHEX mutations lead to increased FGF23 levels remains obscure. FGF23 binds to FGF receptors (FGFR) 1 and 3c in the presence of the accessory receptor Klotho-α. Both Klotho and the FGFR must be present for signaling in most tissues, although high levels of FGF23 appear to affect cardiomyocytes lacking Klotho. Mutations in Klotho disrupt FGF23 signaling, resulting in elevated phosphate and 1,25(OH)2D levels, a phenotype quite similar to inactivating mutations in FGF23 or GALNT3. FGF23 production is stimulated by 1,25(OH)2D and phosphate and directly or indirectly inhibited by the dentin matrix protein DMP1 found in osteocytes. Mutations in DMP1 lead to increased FGF23 levels and osteomalacia.
INTERACTION OF PTH, FGF23, & VITAMIN D