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

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)₂Vitamin D₃ 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)₂Vitamin D₃ levels remained elusive. To determine the FGFRs regulating 1,25(OH)₂Vitamin D₃ 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)₂Vitamin D₃ 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)₂Vitamin D₃ 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)₂Vitamin D₃ 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)₂Vitamin D₃ levels in response to FGF23. In addition, when 1,25(OH)₂Vitamin D₃ 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.