Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1α-hydroxylase expression in vitro

Abstract

August 15, 2007; doi:10.1152/ajprenal.00463.2006) is critical to the pathogenesis of a distinct group of renal phosphate wasting disorders: tumor-induced osteomalacia, X-linked hypophosphatemia, and autosomal dominant and autosomal recessive hypophosphatemic rickets. Excess circulating FGF-23 is responsible for their major phenotypic features which include hypophosphatemia due to renal phosphate wasting and inappropriately low serum 1,25(OH) 2D concentrations. To characterize the effects of FGF-23 on renal sodium-phosphate (Na/P i) cotransport and vitamin D metabolism, we administered FGF-23(R176Q) to normal mice. A single injection (0.33 g/g body wt) induced significant hypophosphatemia, 20 and 29% decreases (P Ͻ 0.001) in brush-border membrane (BBM) Na/P i cotransport at 5 and 17 h after injection, respectively, and comparable decreases in the abundance of type IIa Na/P i cotransporter protein in BBM. Multiple injections (6, 12, and 24 g/day for 4 days) induced dose-dependent decreases (38, 63, and 75%, respectively) in renal abundance of 1␣-hydroxylase mRNA (P Ͻ 0.05). To determine whether FGF-23(R176Q) exerts a direct action on 1␣-hydroxylase gene expression, we examined its effects in cultured human (HKC-8) and mouse (MCT) renal proximal tubule cells. FGF-23(R176Q) (1 to 10 ng/ml) induced a dose-dependent decrease in 1␣-hydroxylase mRNA with a maximum suppression of 37% (P Ͻ 0.05). Suppression was detectable after 6 h of exposure and maximal after 21 h. In MCT cells, FGF-23(R176Q) suppressed 1␣-hydroxylase mRNA and activated the ERK1/2 signaling pathway. The MAPK inhibitor PD98059 effectively abolished FGF-23-induced suppression of 1␣-hydroxylase mRNA by blocking signal transduction via ERK1/2. These novel findings provide evidence that FGF-23 directly regulates renal 1␣-hydroxylase gene expression via activation of the ERK1/2 signaling pathway. bone and mineral homeostasis; hypophosphatemic syndromes FIBROBLAST GROWTH FACTOR-23 (FGF-23), a bone-derived circulating peptide, is an important regulator of phosphorus and 1,25-dihydroxyvitamin D [1,25(OH) 2 D] metabolism and is required for maintenance of normal bone and mineral homeostasis. An excess of FGF-23 has been linked to the pathogenesis of tumor-induced osteomalacia, X-linked hypophosphatemia, and autosomal dominant and autosomal recessive hypophosphatemic rickets (4,12,21,29,33). These hypophosphatemic syndromes share common clinical and laboratory features which include rickets and osteomalacia, hypophosphatemia due to renal phosphate (P i ) wasting, inappropriately low serum 1,25(OH) 2 D concentrations, and greatly increased serum FGF-23 concentrations. That excess circulating FGF-23 contributes to the pathogenesis of these disorders is supported by observations that administration of recombinant FGF-23 or its overexpression in animals induces hypophosphatemia and inhibition of sodium (Na)-dependent P i (Na/P i ) cotransport in renal brush-border membrane (BBM) vesicles (1,19,29). FGF-23 suppresses the renal production of 1,25(OH) 2 D by suppressin...

Forging Forward with 10 Burning Questions on FGF23 in Kidney Disease

“…12 These effects are dependent on the presence of klotho, which is highly expressed in the kidney and the parathyroid glands and acts as a co-receptor for FGF23 by markedly increasing the affinity of FGF23 for ubiquitous FGF receptors. 13,14 These aspects of FGF23 physiology were demonstrated in studies of animals that were administered FGF23, 4,10,12,15 transgenic mice that overexpress FGF23, 16 -19 and klotho 20 and FGF23 null mice. 21 Physiologic studies of normal humans were confirmatory, [22][23][24] as were observations from patients with Published online ahead of print.…”

Striking Pathology Gold: A Singular Experience with Daily Reverberations: Sinonasal Hemangiopericytoma (Glomangiopericytoma) and Oncogenic Osteomalacia

“…The functional FGF23-specific receptor is comprised of Klotho, a senescence-related molecule, and FGFR1(IIIc) [43]. Both PTH and FGF23 decrease phosphate reabsorption in the proximal renal tubule by downregulating expression of the sodium-dependent phosphate transport proteins (Npt2a and Npt2c) [44]. PTH appears to be necessary for fully developed hypophosphatemia, as patients with increased FGF23 but low or undetectable PTH do not develop hypophosphatemia [45].…”

The Human Response to Acute Enteral and Parenteral Phosphate Loads

“…16 The net effect of PO4 loading on 1,25 (OH) 2 D in healthy humans is difficult to predict because hyperphosphatemia and increased FGF-23 were demonstrated to inhibit while increased PTH was shown to stimulate 1a-hydroxylase. [17][18][19] In addition, FGF-23 is positively regulated by 1,25(OH) 2 D, PTH, and Klotho. [20][21][22] This complexity of the PO4-FGF-23 cybernetic system, coupled with the indeterminate evidence for an FGF-23 response to phosphate loads in humans, makes it difficult to predict the relative importance of these four hormones and the temporal relation of their response in the elimination of a PO4 load.…”