Phosphatonins and the Regulation of Phosphate Homeostasis

Abstract

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(+)-P(i)) 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 1alpha,25-dihydroxyvitamin D (1alpha,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(i) excretion, resulting in hypophosphatemia. FGF-23 and sFRP-4 inhibit 25-hydroxyvitamin D 1alpha-hydroxylase activity, reducing 1alpha,25(OH)(2)D(3) synthesis and thus intestinal P(i) absorption. This review examines the role of these factors in P(i) homeostasis in health and disease.

Fibroblast Growth Factor-23 in Early Chronic Kidney Disease

“…Our data confirm and extend data from previous studies showing that an increased renal phosphate excretion in patients with CKD is driven, at least partly, by PTH and FGF-23 (3,(5)(6)(7). Both hormones were inversely associated with eGFR.…”

“…Recent clinical studies demonstrate a high fractional renal phosphate excretion despite the presence of normophosphatemia in early CKD (2)(3)(4). The increased renal phosphate excretion is driven, at least partly, by parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) (3,(5)(6)(7).…”

Functional heterogeneity of osteocytes in FGF23 production: the possible involvement of DMP1 as a direct negative regulator

“…In the kidneys, this hormone reduces the expression of sodium-phosphate transporters (type IIa and IIc) in the renal proximal tubular membrane, thereby downregulating phosphate reabsorption, thus resulting in the excretion of phosphate. 19,20 FGF23 reduces the 1,25-dihydroxyvitamin level by inhibiting the renal 1-a-hydroxylase expression and promoting the 24-hydroxylase expression, thereby downregulating the amount of phosphate absorption from the gut and resorption from the bone. 21,22 Mutual regulation of FGF23 and parathyroid hormone has been reported in rodent models 23,24 and identified in clinical cases of hypophosphatemic rickets and chronic kidney disease.…”

Recovery of Hyperphosphatoninism and Renal Phosphorus Wasting One Year after Successful Renal Transplantation

“…These findings indicate that in progressive renal failure compensatory increases in renal phosphorus excretion are recruited before the development of hyperphosphatemia. This increase in renal phosphorus excretion is driven, at least partly, by parathyroid hormone (PTH) and by FGF-23 (9,(11)(12)(13). Renal transplant recipients (RTR) represent a unique subset of patients with CKD.…”