The phosphatonins and the regulation of phosphate transport and vitamin D metabolism

Phosphate homeostasis is preserved during variations in phosphate intake by short-term intrinsic renal and intestinal adaptations in transport processes, and by more long-term hormonal mechanisms, which regulate the efficiency of phosphate transport in the kidney and intestine. Recently, several phosphaturic peptides such as fibroblast growth factor 23 (FGF-23), secreted frizzled-related protein-4 (sFRP-4), extracellular phosphoglycoprotein (MEPE) and fibroblast growth factor 7 (FGF-7) have been shown to play a pathogenic role in several hypophosphatemic disorders such as tumor-induced osteomalacia (TIO), autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemic rickets (XLH), the McCune–Albright syndrome (MAS) and fibrous dysplasia (FD). These proteins induce phosphaturia and hypophosphatemia in vivo, and inhibit sodium-dependent renal phosphate transport in cultured renal epithelial cells. Interestingly, despite the induction of hypophosphatemia by FGF-23 and sFRP-4 in vivo, serum 1, 25-dihydroxyvitamin D (1α,25(OH)2D) concentrations are decreased or remain inappropriately normal, suggesting an inhibitory effect of these proteins on 25-hydroxyvitamin D 1α-hydroxylase activity. In FGF-23 knockout mice, 25-hydroxyvitamin D 1α-hydroxylase expression is increased and elevated serum 1α,25(OH)2D levels cause significant hypercalcemia and hyperphosphatemia. MEPE, however, increases circulating 1α,25(OH)2D. Circulating or local concentrations of these peptides/proteins may regulate 25-hydroxyvitamin D 1α-hydroxylase activity in renal tissues under physiologic circumstances.