FGF-23 Is a Potent Regulator of Vitamin D Metabolism and Phosphate Homeostasis

Abstract

We analyzed the effects of an FGF‐23 injection in vivo. FGF‐23 caused a reduction in serum 1,25‐dihydroxyvitamin D by altering the expressions of key enzymes for the vitamin D metabolism followed by hypophosphatemia. This study indicates that FGF‐23 is a potent regulator of the vitamin D and phosphate metabolism. Introduction: The pathophysiological contribution of FGF‐23 in hypophosphatemic diseases was supported by animal studies in which the long‐term administration of recombinant fibroblast growth factor‐23 reproduced hypophosphatemic rickets with a low serum 1,25‐dihydroxyvitamin D [1,25(OH)₂D] level. However, there is no clear understanding of how FGF‐23 causes these changes. Materials and Methods: To elucidate the molecular mechanisms of the FGF‐23 function, we investigated the short‐term effects of a single administration of recombinant FGF‐23 in normal and parathyroidectmized animals. Results: An injection of recombinant FGF‐23 caused a reduction in serum phosphate and 1,25(OH)₂D levels. A decrease in serum phosphate was first observed 9 h after the injection and was accompanied with a reduction in renal mRNA and protein levels for the type IIa sodium‐phosphate cotransporter (NaPi‐2a). There was no increase in the parathyroid hormone (PTH) level throughout the experiment, and hypophosphatemia was reproduced by FGF‐23 in parathyroidectomized rats. Before this hypophosphatemic effect, the serum 1,25(OH)₂D level had already descended at 3 h and reached the nadir 9 h after the administration. FGF‐23 reduced renal mRNA for 25‐hydroxyvitamin D‐1α‐hydroxylase and increased that for 25‐hydroxyvitamin D‐24‐hydroxylase starting at 1 h. In addition, an injection of calcitriol into normal mice increased the serum FGF‐23 level within 4 h. Conclusions: FGF‐23 regulates NaPi‐2a independently of PTH and the serum 1,25(OH)₂D level by controlling renal expressions of key enzymes of the vitamin D metabolism. In conclusion, FGF‐23 is a potent regulator of phosphate and vitamin D homeostasis.