Endocrine Abstracts

Fibroblast growth factor 23 (FGF23) is a phosphotropic hormone that belongs along with FGF19 and 21 to a subfamily of endocrine FGFs with evolutionary conserved functions, which can be demonstrated in the gut of C. elegans and in the kidney tubules of fruit flies. FGF23 is posttranslationally regulated by phosphorylation through FAM20C, which causes its proteolysis through the subtilisin-like proprotein convertase FURIN, and results in secretion of FGF23 fragments. O-glycosylation of FGF23 through GALNT3 in turn appears to prevent proteolysis resulting in secretion of the biologically active intact FGF23, that may undergo further processing by plasminogen activators in the circulation. Crystal structures show that the ectodomain of the cognate FGF23 receptor FGFR1c binds with the ectodomain of the co-receptor alpha KLOTHO to create a high affinity binding site for the C-terminal tail of FGF23. The topology of FGF23 furthermore deviates from that of paracrine FGFs, resulting in poor affinity for heparan sulfate, which may explain why FGF23 can diffuse freely in the bone matrix to enter into the bloodstream following it’s secretion by cells of the osteoblastic lineage. Intact FGF23 signalling by this canonical pathway activates FRS2/RAS/RAF/MEK/ERK1/2 and reduces serum phosphate by inhibiting 1,25-dihydroxyvitamin D synthesis, which suppresses intestinal phosphate absorption, and by down regulating the transporters NPT2a and NPT2c, which suppresses phosphate reabsorption in the proximal tubules of the kidneys. The physiological role of FGF23 fragments, which may be inhibitory, is currently unclear. Pharmacological and genetic activation of canonical FGF23 signaling causes hypophosphatemic disorders, while it’s inhibition results in hyperphosphatemic disorders. In addition, non-canonical FGF23 signaling through binding and activation of FGFR4/calcineurin/NFAT in an alpha KLOTHO independent fashion was reported, which mainly occurs at extremely elevated circulating FGF23 levels, and may contribute to mortality due to cardiovascular disease and left ventricular hypertrophy in chronic kidney disease.