Phosphatonins and the regulation of phosphate homeostasis

Inorganic phosphate (P-i) is required for energy metabolism, nucleic acid synthesis, bone mineralization, and cell signaling. The activity of cell-surface sodium-phosphate (Na+-Pi) cotransporters mediates the uptake of P-i from the extracellular environment. Na+-P-i cotransporters and organ-specific P-i absorptive processes are regulated by peptide and sterol hormones, such as parathyroid hormone (PTH) and 1 alpha,25-dihydroxyvitamin D (1 alpha,25(OH)(2)D-3), which interact in a coordinated fashion to regulate P-i homeostasis. Recently, several phosphaturic peptides such as fibroblast growth factor-23 (FGF-23), secreted frizzled related protein-4 (sFRP-4), matrix extracellular phosphoglycoprotein, and fibroblast growth factor-7 have been demonstrated to play a pathogenic role in several hypophosphatemic disorders. By inhibiting Na+-P-i transporters in renal epithelial cells, these proteins increase renal P; excretion, resulting in hypophosphaternia. FGF-23 and sFRP-4 inhibit 25-hydroxyvitamin D 1 alpha-hydroxylase activity, reducing 1 alpha,25(OH)(2)D-3 synthesis and thus intestinal P-i absorption. This review examines the role of these factors in P-i homeostasis vi health and disease.