Phosphatonins: new hormones that control phosphorus homeostasis

Phosphorus (Pi) plays an important role in nucleic acid synthesis, energy metabolism, bone mineralization and cell signaling, and is also present in sugars, phospholipids and phosphoproteins. Phosphate homeostasis is controlled by processes that regulate the intestinal absorption and renal excretion of Pi, and bone turnover. These processes are influenced by peptide and sterol hormones, such as parathyroid hormone and 1α,25-dihydroxyvitamin D (1α,25[OH]₂D₃). Recently, a new class of phosphate-regulating peptides has been discovered: phosphatonins. These factors, such as FGF-23, secreted frizzled-related protein-4, matrix extracellular phosphoglycoprotein and FGF-7, are circulating peptides with potent phosphaturic activity. These peptides inhibit Na/Pi transporters in renal epithelial cells and, therefore, increase renal Pi excretion. In addition, FGF-23 and secreted frizzled-related protein-4 inhibit 25-hydroxyvitamin D 1α-hydroxylase activity, reducing 1α,25(OH)2D3 synthesis and, thus, intestinal Pi absorption. Phosphatonins have been associated with hypophosphatemic diseases, such as tumor-induced osteomalacia, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets and hyperphosphatemic disease (e.g., tumoral calcinosis). The aim of this article is to review the role of phosphatonins in Pi metabolism in normal and pathologic conditions and also to investigate the correlations among the various phosphatonins.