Fibrous dysplasia and fibroblast growth factor-23 regulation

Abstract

Fibrous dysplasia (FD) is a skeletal disorder caused by activating mutations in Gsα that result in elevations in cAMP. A feature of FD is elevated blood levels of the bone cell-derived phosphaturic hormone, fibroblast growth factor-23 (FGF23). FGF23 regulates serum phosphorus and active vitamin D levels by action on proximal renal tubule cells. An essential step in the production of biologically active FGF23 is glycosylation by the UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyl transferase (ppGalNAc-T3). In the absence of glycosylation, FGF23 is processed into inactive N- and C-terminal proteins by a subtilisin proprotein convertase, probably furin. Normally, most if not all circulating FGF23 is intact. In FD, C-terminal levels are elevated, suggesting altered FGF23 processing. Altered processing in FD is the result of a cAMP-dependent, coordinated decrease in ppGalNAc-T3 and an increase in furin enzyme activity. These findings, and emerging data from other diseases, suggest regulation of FGF23 processing may be a physiologically important process.

Figure

Bone cells (osteocytes and osteoblasts) are responsible for production of FGF23 (blue boxes). The galactosyl transferase UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyl transferase (GALNT3, green box) glycosylates FGF23 and by doing so protects it from enzymatic degradation by a subtilisin proprotein convertase, probably furin (scissors). Unglycosylated, unprotected FGF23 (lower blue box) is degraded and C- and N-terminal degradation products (probably biologically inactive) are secreted into the circulation. In fibrous dysplasia, under the regulation of cAMP, the process of degradation is enhanced (blue arrow). This degradation process may also be increased in low iron states, possibly mediated by the HIF-1 pathway.