Fibroblast growth factor 23 regulates renal 1,25-dihydroxyvitamin D and phosphate metabolism via the MAP kinase signaling pathway in Hyp mice

Abstract

In X-linked hypophosphatemia (XLH) and in its murine homologue, the Hyp mouse, increased circulating concentrations of fibroblast growth factor 23 (FGF-23) are critical to the pathogenesis of disordered metabolism of phosphate (Pi) and 1,25-dihydroxyvitamin D [1,25(OH)2D]. In this study, we hypothesized that in Hyp mice, FGF-23-mediated suppression of renal 1,25(OH)2D production and Pi reabsorption depends on activation of mitogen-activated protein kinase (MAPK) signaling. Wild-type and Hyp mice were administered either vehicle or the MEK inhibitor PD0325901 (12.5 mg/kg) orally daily for 4 days. At baseline, the renal abundance of early growth response 1 (egr1) mRNA was approximately 2-fold greater in Hyp mice than in wild-type mice. Treatment with PD0325901 greatly suppressed egr1 mRNA abundance in both wild-type and Hyp mice. In Hyp mice, PD0325901 induced an 8-fold increase in renal 1α-hydroxylase mRNA expression and a 4-fold increase in serum 1,25(OH)2D concentrations compared with vehicle-treated Hyp mice. Serum Pi levels in Hyp mice increased significantly after treatment with PD0325901, and the increase was associated with increased renal Npt2a mRNA abundance and brush-border membrane Npt2a protein expression. These findings provide evidence that in Hyp mice, MAPK signaling is constitutively activated in the kidney and support the hypothesis that the FGF-23-mediated suppression of renal 1,25(OH)2D production and Pi reabsorption depends on activation of MAPK signaling via MEK/ERK1/2. These findings demonstrate the physiologic importance of MAPK signaling in the actions of FGF-23 in regulating renal 1,25(OH)2D and Pi metabolism.

FGF23-FGF Receptor/Klotho Pathway as a New Drug Target for Disorders of Bone and Mineral Metabolism

“…FGF receptor can activate several signal transduction pathways including phosphorylation of mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase, and phospholipase Cc [42]. The inhibitor of MAPK, PD0325901, was shown to increase serum phosphate and 1,25(OH) 2 D levels in Hyp mice [6]. Long-term treatment with the inhibitor enhanced mineralization and increased bone mineral density of Hyp mice [9].…”

“…These findings suggest that FGF23-FGF receptor/Klotho pathway can be a new drug target for disorders of mineral and bone metabolism. Actually, several preclinical studies indicated that the inhibition of FGF23 activities may be useful for hypophosphatemic diseases caused by excessive actions of FG23 [3][4][5][6][7][8][9]. In addition, the results of phase I-II clinical trials of neutralizing anti-FGF23 antibody were published [10,11].…”

FGF23-Klotho signaling axis in the kidney

“…In Hyp mice, a mouse model of the human disease XLH which is characterized by increased endogenous Fgf23 secretion, it was shown that the elevated serum Fgf23 levels are correlated with increased ERK1/2 signaling, and that blockade of ERK1/2 in the kidney of Hyp mice improves hypophosphatemia, 1,25(OH) 2 D deficiency, and the skeletal mineralization defects [56,57]. The transcription factor egr-1 is a downstream target of FGF23-induced ERK1/2 activation [14].…”

Fibroblast Growth Factor 23

“…2). 18,149,217 These signals lead to phosphorylation of the Na þ /H þ exchange regulatory cofactor (NHERF) 1, which causes existing cotransporters to be removed from the brush-border membrane of renal tubular epithelial cells, and reduced expression of renal tubular Na/P II cotransporters. 6,139 In addition, the ERK-1/2 pathway (induced by FGF23) downregulates renal 1a-hydroxylase expression.…”