Fibroblast growth factor-23 (FGF-23) is critical to the pathogenesis of a distinct group of renal phosphate wasting disorders: tumor-induced osteomalacia, X-linked hypophosphatemia, and autosomal dominant and autosomal recessive hypophosphatemic rickets. Excess circulating FGF-23 is responsible for their major phenotypic features which include hypophosphatemia due to renal phosphate wasting and inappropriately low serum 1,25(OH)₂D concentrations. To characterize the effects of FGF-23 on renal sodium-phosphate (Na/Pi) cotransport and vitamin D metabolism, we administered FGF-23(R176Q) to normal mice. A single injection (0.33 µg/g BW) induced significant hypophosphatemia, 20% and 29% decreases (p<0.001) in BBM Na/Pi cotransport at five and seventeen hours after injection, respectively, and comparable decreases in the abundance of type IIa Na/Pi cotransporter protein in BBM. Multiple injections (6, 12, and 24 µg/day for 4 days) induced dose-dependent decreases (38%, 63%, and 75%, respectively) in renal abundance of 1-hydroxylase mRNA (p<0.05). To determine whether FGF-23(R176Q) exerts a direct action on 1-hydroxylase gene expression, we examined its effects in cultured human (HKC-8) and mouse (MCT) renal proximal tubule cells. FGF-23(R176Q) (1 to 10 ng/ml) induced a dose-dependent decrease in 1-hydroxylase mRNA with a maximum suppression of 37% (P<0.05). Suppression was detectable after 6 hours of exposure and maximal after 21 hours. In MCT cells, FGF-23(R176Q) suppressed 1-hydroxylase mRNA and activated the ERK1/2 signaling pathway. The MAPK inhibitor PD98059, effectively abolished FGF-23-induced suppression of 1-hydroxylase mRNA by blocking signal transduction via ERK1/2. These novel findings provide evidence that FGF-23 directly regulates renal 1-hydroxylase gene expression via activation of the ERK1/2 signaling pathway.