Fibroblast Growth Factor 23 Is a Counter-Regulatory Phosphaturic Hormone for Vitamin D

The regulation of the phosphaturic factor fibroblast growth factor 23 (FGF23) is not well understood. It was found that administration of 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) to mice rapidly increased serum FGF23 concentrations from a basal level of 90.6 ± 8.1 to 213.8 ± 14.6 pg/ml at 8 h (mean ± SEM; P < 0.01) and resulted in a four-fold increase in FGF23 transcripts in bone, the predominate site of FGF23 expression. In the Hyp-mouse homologue of X-linked hypophosphatemic rickets, administration of 1,25(OH)2D3 further increased circulating FGF23 levels. In Gcm2 null mice, low 1,25(OH)2D3 levels were associated with a three-fold reduction in FGF23 levels that were increased by administration of 1,25(OH)2D3. In osteoblast cell cultures, 1,25(OH)2D3 but not calcium, phosphate, or parathyroid hormone stimulated FGF23 mRNA levels and resulted in a dose-dependent increase in FGF23 promoter activity. Overexpression of a dominant negative vitamin D receptor inhibited 1,25(OH)2D3 stimulation of FGF23 promoter activity, and mutagenesis of the FGF23 promoter identified a vitamin D-responsive element (−1180 GGAACTcagTAACCT −1156) that is responsible for the vitamin D effects. These data suggest that 1,25(OH)2D3 is an important regulator of FGF23 production by osteoblasts in bone. The physiologic role of FGF23 may be to act as a counterregulatory phosphaturic hormone to maintain phosphate homeostasis in response to vitamin D.