1,25-Dihydroxyvitamin D (1,25(OH)(2)D) plays a critical role in calcium and phosphorus (Pi) metabolism, bone growth, and tissue differentiation. The synthesis of 1,25(OH)(2)D in the proximal renal tubule is the primary determinant of its circulating concentration and is mediated by the mitochondrial enzyme, 25-hydroxyvitamin D-1α-hydroxylase, CYP27B1). Enzyme activity in the kidney is tightly regulated by several factors, of which Pi and fibroblast growth factor 23 (FGF-23) are important determinants. In healthy human subjects and experimental animals, dietary Pi restriction and resultant hypophosphatemia stimulate renal 1,25(OH)(2)D production by transcriptional up regulation of the 1α-hydroxylase gene, and this effect is independent of serum concentrations of PTH. Dietary Pi intake and serum Pi concentration also are important determinants of the circulating concentration of FGF-23, itself a potent regulator of Pi and vitamin D metabolism. In several inherited human hypophosphatemic diseases, including X-linked hypophosphatemia, serum FGF-23 concentrations are increased, resulting in renal Pi wasting, hypophosphatemia, inappropriately low serum concentrations of 1,25(OH)(2)D, and growth retardation and rickets in children. Experimental studies demonstrate that direct administration of recombinant FGF-23 or its over-expression in mice induces a dose-dependent decrease in renal CYP27B1 mRNA expression, an increase in renal 24-hydroxylase mRNA expression, and a consequent decrease in serum 1,25(OH)(2)D concentrations. Studies in vitro and in vivo demonstrate that activation of MEK/ERK1/2 signaling in the kidney is necessary for the suppression of CYP27B1 gene expression by FGF-23. Thus, phosphorus and FGF-23 are important physiologic determinants of the renal metabolism of 1,25(OH)(2)D.
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