The phosphatonins and the regulation of phosphate transport and vitamin D metabolism |
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Authors: | Sommer Stacy Berndt Theresa Craig Theodore Kumar Rajiv |
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Institution: | Nephrology and Hypertension Research, Department of Medicine, Biochemistry and Molecular Biology, Mayo Clinic, MS 1-120, 200 First Street SW, Rochester, MN 55905, USA. |
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Abstract: | 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 (1alpha,25(OH)(2)D) concentrations are decreased or remain inappropriately normal, suggesting an inhibitory effect of these proteins on 25-hydroxyvitamin D 1alpha-hydroxylase activity. In FGF-23 knockout mice, 25-hydroxyvitamin D 1alpha-hydroxylase expression is increased and elevated serum 1alpha,25(OH)(2)D levels cause significant hypercalcemia and hyperphosphatemia. MEPE, however, increases circulating 1alpha,25(OH)(2)D. Circulating or local concentrations of these peptides/proteins may regulate 25-hydroxyvitamin D 1alpha-hydroxylase activity in renal tissues under physiologic circumstances. |
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Keywords: | Fibroblast growth factor 23 Secreted frizzled related protein-4 Matrix extracellular phosphoglycoprotein and fibroblast growth factor 7 Phosphate 25-Hydroxyvitamin D 1α -hydroxylase 1 25-Dihydroxyvitamin D (1α 25(OH)2D) Tumor-induced osteomalacia Autosomal dominant hypophosphatemic rickets (ADHR) X-linked hypophosphatemic rickets (XLH) Phosphate (Pi) |
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