Regulation of serum 1,25(OH)2 vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4

Abstract

Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in the pathogenesis of several hypophosphatemic disorders. FGF23 causes hypophosphatemia by decreasing the expression of sodium phosphate cotransporters (NaPi-2a and NaPi-2c) and decreasing serum 1,25(OH)(2)Vitamin D(3) levels. We previously showed that FGFR1 is the predominant receptor for the hypophosphatemic actions of FGF23 by decreasing renal NaPi-2a and 2c expression while the receptors regulating 1,25(OH)(2)Vitamin D(3) levels remained elusive. To determine the FGFRs regulating 1,25(OH)(2)Vitamin D(3) levels, we studied FGFR3(-/-)FGFR4(-/-) mice as these mice have shortened life span and are growth retarded similar to FGF23(-/-) and Klotho(-/-) mice. Baseline serum 1,25(OH)(2)Vitamin D(3) levels were elevated in the FGFR3(-/-)FGFR4(-/-) mice compared with wild-type mice (102.2 ± 14.8 vs. 266.0 ± 34.0 pmol/l; P = 0.001) as were the serum levels of FGF23. Administration of recombinant FGF23 had no effect on serum 1,25(OH)(2)Vitamin D(3) in the FGFR3(-/-)FGFR4(-/-) mice (173.4 ± 32.7 vs. 219.7 ± 56.5 pmol/l; vehicle vs. FGF23) while it reduced serum 1,25(OH)(2)Vitamin D(3) levels in wild-type mice. Administration of FGF23 to FGFR3(-/-)FGFR4(-/-) mice resulted in a decrease in serum parathyroid hormone (PTH) levels and an increase in serum phosphorus levels mediated by increased renal phosphate reabsorption. These data indicate that FGFR3 and 4 are the receptors that regulate serum 1,25(OH)(2)Vitamin D(3) levels in response to FGF23. In addition, when 1,25(OH)(2)Vitamin D(3) levels are not affected by FGF23, as in FGFR3(-/-)FGFR4(-/-) mice, a reduction in PTH can override the effects of FGF23 on renal phosphate transport.

Fig. 1.

Renal cortical brush-border membrane (BBM) NaPi-2a expression in wild-type and fibroblast growth factor receptor (FGFR)3^−/−FGFR4^−/− mice at baseline. NaPi-2a expression normalized to β-actin analyzed by immunoblotting is shown here. BBM NaPi-2a expression was lower in the FGFR3^−/−FGFR4^−/− mice. Bars represent means and SE.

Fig. 2.

Acute effects of FGF23 on renal cortical BBM NaPi-2a expression in wild-type and FGFR3^−/−FGFR4^−/− mice. NaPi-2a expression normalized to β-actin performed by immunoblotting is shown here. In response to FGF23, as anticipated, renal cortical BBM NaPi-2a expression decreased significantly in the wild-type mice. In FGFR3^−/−FGFR4^−/− mice, upon FGF23 administration, keeping with the serum phosphorus levels, renal cortical BBM NaPi-2a expression increased. Bars represent means and SE.

Fig. 3.

Acute effects of FGF23 on renal cortical BBM vesicle (BBMV) phosphate transport in wild-type and FGFR3^−/−FGFR4^−/− mice. Renal BBMVs were examined for phosphate transport using ³²P as described in methods. To 100 μg of BBMV loaded in an intravesicular buffer, an extravesicular buffer containing ³²P was added. Phosphate transport was terminated using ice-cold stop solution. As shown in this graph, the BBMV phosphate transport is decreased in response to FGF23 in the wild-type mice but the phosphate transport is increased in FGFR3^−/−FGFR4^−/− mice. This is in keeping with the serum phosphorus levels and BBM NaPi-2a expression.