Dept. of Pediatrics, U.T. Southwestern Medical Center, Dallas, TX 75390-9063, USA.
Am J Physiol Renal Physiol. 2011 Aug;301(2):F371-7. doi: 10.1152/ajprenal.00740.2010. Epub 2011 May 11.
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.
成纤维细胞生长因子 23（FGF23）是一种致低磷血症的激素，与多种低磷血症疾病的发病机制有关。FGF23 通过降低钠磷共转运蛋白（NaPi-2a 和 NaPi-2c）的表达和降低血清 1,25（OH）（2）维生素 D（3）水平导致低磷血症。我们之前的研究表明，FGFR1 通过降低肾脏 NaPi-2a 和 2c 的表达来介导 FGF23 的致低磷作用，而调节 1,25（OH）（2）维生素 D（3）水平的受体仍不清楚。为了确定调节 1,25（OH）（2）维生素 D（3）水平的 FGFR，我们研究了 FGFR3（-/-）FGFR4（-/-）小鼠，因为这些小鼠的寿命缩短且生长迟缓，类似于 FGF23（-/-）和 Klotho（-/-）小鼠。与野生型小鼠相比，FGFR3（-/-）FGFR4（-/-）小鼠的基础血清 1,25（OH）（2）维生素 D（3）水平升高（102.2 ± 14.8 对 266.0 ± 34.0 pmol/l；P = 0.001），血清 FGF23 水平也升高。重组 FGF23 对 FGFR3（-/-）FGFR4（-/-）小鼠的血清 1,25（OH）（2）维生素 D（3）水平没有影响（173.4 ± 32.7 对 219.7 ± 56.5 pmol/l；载体对 FGF23），而它降低了野生型小鼠的血清 1,25（OH）（2）维生素 D（3）水平。FGF23 给药至 FGFR3（-/-）FGFR4（-/-）小鼠导致血清甲状旁腺激素（PTH）水平降低和血清磷水平升高，这是通过增加肾脏磷酸盐重吸收介导的。这些数据表明，FGFR3 和 4 是响应 FGF23 调节血清 1,25（OH）（2）维生素 D（3）水平的受体。此外，当 1,25（OH）（2）维生素 D（3）水平不受 FGF23 影响时，如在 FGFR3（-/-）FGFR4（-/-）小鼠中，PTH 的降低可以抵消 FGF23 对肾脏磷酸盐转运的影响。
