Figure 1. Regulation and action of fibroblast growth factor 23 (FGF23).

Bone cells are the primary cells that synthesize and secrete FGF23. There are a number of systemic stimuli of FGF23 secretion—increased dietary phosphorus absorption, increased 1,25-dihydroxyvitamin D concentrations, and circulating Klotho. The effects of parathyroid hormone on FGF23 are more controversial, with some studies suggesting that parathyroid hormone directly stimulates FGF23 while others do not. FGF23 acts primarily in the kidneys and parathyroid glands. In the kidneys, FGF23 augments urinary phosphate excretion by down-regulating sodium-phosphate co-transporters in renal proximal tubular cells. In addition, FGF23 inhibits the synthesis of CYP27B1 and up-regulates CYP24A1, both of which serve to decrease circulating 1,25-dihydroxyvitamin D concentrations. In the parathyroid glands, FGF23 inhibits both the synthesis and secretion of parathyroid hormone. Transmembrane Klotho is needed for FGF23 to bind to its receptor in the kidney and parathyroid glands with high-enough affinity to effect signal transduction (dashed lines in the figure). The actions of FGF23 on the kidney and parathyroid glands appear to serve the primary purpose of maintaining phosphorus homeostasis in kidney disease by enhancing urinary phosphate excretion and decreasing intestinal phosphorus absorption via lower 1,25-dihydroxyvitamin D concentrations.