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Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1-hydroxylase expression in vitro

¹Pediatrics, University of California San Francisco, San Francisco, California; and ²Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada

Submitted 20 November 2006 ; accepted in final form 9 August 2007

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/P_i) cotransport and vitamin D metabolism, we administered FGF-23(R176Q) to normal mice. A single injection (0.33 µg/g body wt) induced significant hypophosphatemia, 20 and 29% decreases (P < 0.001) in brush-border membrane (BBM) Na/P_i cotransport at 5 and 17 h after injection, respectively, and comparable decreases in the abundance of type IIa Na/P_i 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 h of exposure and maximal after 21 h. 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.

bone and mineral homeostasis; hypophosphatemic syndromes

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