Fibroblast Growth Factor (FGF)-23 Inhibits Renal Phosphate Reabsorption by Activation of the Mitogen-activated Protein Kinase Pathway

Abstract

The homeostasis of the plasma phosphate level is essential for many biological processes including skeletal mineralization. The reabsorption of phosphate in the kidney is a major determinant of the plasma levels of phosphate. Phosphatonin is a hormone-like factor that specifically inhibits phosphate uptake in renal proximal epithelial cells. Recent studies on tumor-induced osteomalacia suggested that phosphatonin was potentially identical to fibroblast growth factor (FGF)-23. However, as purified recombinant FGF-23 could not inhibit phosphate uptake in renal proximal epithelial cells, the mechanism of action of FGF-23 remains to be elucidated. Therefore, we examined the mechanism of action of FGF-23 in cultured renal proximal epithelial cells, opossum kidney cells. FGF-23 was found to require heparinlike molecules for its inhibitory activity on phosphate uptake. FGF-23 binds to the FGF receptor 3c, which is mainly expressed in opossum kidney cells, with high affinity. An inhibitor for tyrosine kinases of the FGF receptor, SU 5402, blocked the activity of FGF-23. FGF-23 activated the mitogen-activated protein kinase (MAPK) pathway, which is the major intracellular signaling pathway of FGF. Inhibitors of the MAPK pathway, PD98059 and SB203580, also blocked the activity of FGF-23.ThepresentfindingshaverevealedanovelMAPKdependent mechanism of the regulation of phosphate uptake by FGF signaling.Phosphate is a nutrient essential for many biological processes including skeletal mineralization and energy metabolism (1). The homeostasis of the plasma phosphate level is essential for these processes. The reabsorption of phosphate in the kidney is a major determinant of the plasma phosphate level. Reabsorption is largely regulated by the type II sodium-dependent phosphate (Na/P i ) cotransporter that is expressed in renal proximal epithelial cells (1). The activity of the type-II Na/P i cotransporter is regulated by hormones, such as parathyroid hormone (PTH) 1 and 1,25-dihydroxyvitamin D (1,25(OH) 2 D), which have opposite effects. PTH and 1,25(OH) 2 D decrease and increase the reabsorption of phosphate in renal proximal tubules, respectively (1). Tumor-induced osteomalacia is a renal phosphate-wasting disorder resulting in low serum phosphorus concentration and osteomalacia. Removal of the tumors responsible for tumorinduced osteomalacia normalizes phosphate metabolism. The responsible tumors secrete a heat-sensitive molecule of ϳ25 kDa designated as "phosphatonin" that specifically inhibits sodium-dependent phosphate transport in cultured renal proximal epithelial cells. Recent studies on tumor-induced osteomalacia revealed that phosphatonin was potentially identical to fibroblast growth factor (FGF)-23, which is a new member of the FGF family (2, 3, 5). Autosomal dominant hypophosphataemic rickets is also a renal phosphate-wasting disorder resulting in low serum phosphorus concentration, rickets, and osteomalacia. The ADHR gene was also potentially identified to be FGF-23 with missense mutations (4). However, as puri...

Premature aging‐like phenotype in fibroblast growth factor 23 null mice is a vitamin D‐mediated process

“…Cleavage of the intact 30 kDa-secreted protein results in two smaller fragments of ~18 kDa (amino fragment) and 12 kDa (carboxy fragment) of yet unknown function. Although various studies have shown that FGF-23 can exert certain activities through binding to the known receptors for other members of the FGF family (13,14), the search for a novel receptor that specifically mediates the actions of FGF-23 is ongoing. Genetic modifications of FGF-23 in animals have shown phenotypes similar to those of human diseases.…”

Biological activity of FGF-23 fragments

“…FGF23 contains a consensus binding domain for FGFRs and several studies have suggested that FGF23 may bind and activate signaling through one or more FGFRs [31][32][33]. Recent in vivo genetic manipulation studies suggest that both FGF23 and KLOTHO act through a common signaling pathway [30] and that KLOTHO facilitates FGF23 binding to an FGFR [34].…”

Disorders of Renal Tubular Phosphate Transport

“…Recombinant FGF-23 either had no effect (72) or inhibited (38,68) Na/P i cotransport in OK cells. Moreover, the inhibition that was observed was either prevented (68) or dependent (38) on the presence of heparin in the incubation medium. In the latter study, it was demonstrated that FGF-23 bound to FGF receptor 3c and that inhibition of Na/P i cotransport was mediated by a MAPK signaling pathway (38).…”

“…Studies in opossum kidney (OK) cells demonstrated that the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway also participates in PTH-induced signaling (37). In addition, FGF-23, a factor contributing to renal P i wasting in autosomal dominant hypophosphatemic rickets and oncogenic hypophosphatemic osteomalacia (see below), inhibits type IIa-mediated Na/P i cotransport in OK cells via activation of MAPK (38). Moreover, it was recently documented in isolated perfused cortical slices that the different signaling pathways (PK-A, PK-C, PK-G) converge on the ERK/MAPK pathway to internalize type IIa protein (D. Bacic, C. Wagner, J. Biber, H. Murer; submitted).…”