Figure 5. The bone-kidney-parathyroid endocrine axes mediated by FGF23 and 1,25(OH)₂D₃.

FGF23 is primarily produced in the bones (osteocyte). Through circulation, FGF23 is transferred to the kidney, where it interacts with the FGFRs in the presence of co-receptor Klotho[26]^–[28], decreasing the expression of an electrogenic phosphate transporter (sodium-dependent phosphate transporter 2a, NaPi-2a)[29]^,[30] and an electroneutral phosphate transporter (NaPi-2c) on the apical surface of the proximal tubule and leading to inhibition of renal phosphate reabsorption and 1,25(OH)₂D₃ synthesis[15]^,[27]. This results in phosphaturia and reduced intestinal absorption of calcium and phosphate, eventually decreasing the plasma Pi (inorganic phosphate) and resulting in hypophosphatemia[31]. On the other hand, serum parathyroid hormone (PTH) stimulates while FGF23 inhibits 1,25(OH)₂D₃ production in the kidney[11]^,[32]. In turn, 1,25(OH)₂D₃ inhibits PTH production and secretion from the parathyroid glands and stimulates FGF23 production from the bone as a negative feedback mechanism[33]^,[34]. FGF23 can also decrease PTH secretion, and PTH can decrease the expression of NaPi-2a and NaPi-2c[35]. The red arrows indicate positive regulation, and the gray arrows indicate negative regulation.