Fibroblast Growth Factor 23 Is a Counter-Regulatory Phosphaturic Hormone for Vitamin D

Abstract

The regulation of the phosphaturic factor fibroblast growth factor 23 (FGF23) is not well understood. It was found that administration of 1,25-dihydroxyvitamin D 3 (1,25[OH] 2 D 3 ) to mice rapidly increased serum FGF23 concentrations from a basal level of 90.6 ؎ 8.1 to 213.8 ؎ 14.6 pg/ml at 8 h (mean ؎ SEM; P < 0.01) and resulted in a four-fold increase in FGF23 transcripts in bone, the predominate site of FGF23 expression. In the Hyp-mouse homologue of X-linked hypophosphatemic rickets, administration of 1,25(OH) 2 D 3 further increased circulating FGF23 levels. In Gcm2 null mice, low 1,25(OH) 2 D 3 levels were associated with a three-fold reduction in FGF23 levels that were increased by administration of 1,25 ( FGF23 also suppresses 1␣ hydroxylase activity in the proximal renal tubule, leading to reduced circulating levels of 1,25(OH) 2 D 3 (2,10,14,15). The significance of FGF23 regulation of 1,25(OH) 2 D 3 production is not clear, but the findings that FGF23 is produced predominantly by osteoblasts in bone and that FGF23 regulates phosphate reabsorption and 1,25(OH) 2 D 3 production by the kidney raise the possibility that FGF23 may be involved in a bone-kidney axis that controls phosphate and vitamin D homeostasis (16,17). How FGF23 is integrated with the vitamin D-parathyroid hormone (PTH) axis, which plays a central role in calcium homeostasis, skeletal development, and mineralization (18), however, is not clear. Understanding the effects of 1,25(OH) 2 D 3 on FGF23 production is important, because vitamin D therapy often is used to treat FGF23-mediated hypophosphatemic disorders, such as XLH (19).In an effort to understand more fully the regulation of FGF23 expression in osteoblasts and bone, we assessed the effect of 1,25(OH) 2 D 3 administration on circulating levels of FGF23 in wild-type Gcm2 null (20) and Hyp mice (21), as well as the effects of 1,25(OH) 2 D 3 on the FGF23 transcripts in bone. In addition, we investigated the ability of 1,25(OH) 2 D 3 to regulate endogenous FGF23 transcripts and the activity of a transfected murine FGF23 promoter luciferase reporter in osteoblasts. Our findings demonstrate the importance of bone as a target for vitamin D-mediated increments in FGF23 production and suggest that FGF23 production serves as a counterregulatory hormone to enhance renal phosphate clearance in response to vitamin D-mediated increments in gastrointestinal phosphate absorption and decrements in the phosphaturic hormone PTH. Materials and Methods 1,25(OH) 2 D 3 and PTH AdministrationBoth Hyp mice (21) and C57BL/6J mice were purchased from Jackson Laboratory (Bar Harbor, ME). Male and female Gcm2 ϩ/Ϫ mice were mated to generate homozygous Gcm2 null mice that lacked parathyroid glands (22). All mice were maintained and used in accordance with recommendations in

Premature aging in klotho mutant mice: Cause or consequence?

“…In the same line, when vitamin-D activities were genetically ablated from Fgf-23 null mice by deleting the 1α(OH)ase gene (Fgf-23 −/− /1α(OH)ase −/− compound mutants), most of the premature aging-like features in Fgf-23 null mice were rescued Razzaque et al, 2005); the phenotype of Fgf-23 −/− /1α(OH)ase −/− double mutants resulted in the disappearance of ectopic calcifications from heart, kidney, and lung (Fig-2); moreover, the generalized atrophic changes in skin, intestine and other organs of Fgf-23 null mice were rescued in Fgf-23 −/− /1α(OH)ase −/− double mutants, and the resultant effect being increased overall survival of vitamin-D ablated Fgf-23 null mice. It is, therefore, reasonable to conclude that most of the premature aging-like features in Fgf-23 null and klotho mutant mice are due to hypervitaminosis-D which is most likely the consequence of lack of activity of its counter regulatory hormone, i.e., Fgf-23 (Liu et al, 2006;Saito et al, 2005).…”

“…Furthermore, altered glucose/insulin homeostasis observed in klotho deficient and Fgf-23 null mice can be markedly improved by reducing vitamin-D activities from these mutants, suggesting that altered glucose/insulin homeostasis in klotho-mutant and Fgf-23 null mice is indeed a secondary effect caused by the increased vitamin-D activities in these mice (Hesse et al, 2006;Tsujikawa et al, 2003). It has, therefore, become increasingly clear that premature aging-like features in klotho mutants are caused by the inability of Fgf-23 to exert its effects, that lead to increased activity of its counter regulatory hormone, 1,25(OH) 2 D 3 (Liu et al, 2006), resulting in altered mineral ion homeostasis to produce most of the premature aging-like features.…”

Is fibroblast growth factor 23 a new cardiovascular risk marker in gestational diabetes?

“…One possible mechanism is the involvment of FGF23 in the complex process of vascular calcification (20). 1,25(OH) 2 D 3 is the primary regulator of FGF23 production via osteoblasts in bone, and increased FGF23 levels cause a reduction in 1,25(OH)2D3 levels (21). The decrease in 1,25(OH) 2 D 3 can cause elevated angiotensin II production via an increase in renin expression, which results in hypertension and cardiac hypertrophy (22)(23)(24).…”

Blood Pressure, Proteinuria, and Phosphate as Risk Factors for Progressive Kidney Disease: A Hypothesis

“…However, the molecular mechanisms underlying the association between prolonged phosphate load and increased levels of FGF-23, which is secreted mainly by bone cells, 58 are largely unknown. The responsiveness of FGF-23 to dietary phosphate is sluggish (hours to days), 59 and phosphate does not directly stimulate FGF-23 expression in osteoblast cultures, 60 emphasizing the importance of other local or systemic regulators. 61 Higher FGF-23 levels increase urinary phosphate excretion by suppressing the expression of the sodium-dependent phosphate cotransporters NPT2a and NPT2c in the kidney proximal tubule 61 and reduce phosphorus absorption in the gut by decreasing calcitriol levels.…”