Regulation of serum 1,25(OH)2Vitamin D3 levels by fibroblast growth factor

Gattineni J, Twombley K, Goetz R, Mohammadi M, Baum M. Regulation of serum 1,25(OH)2Vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4. Am J Physiol Renal Physiol 301: F371–F377, 2011. First published May 11, 2011; doi:10.1152/ajprenal.00740.2010.—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.