Du E, Xiao L, Hurley M M
Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut.
J Cell Physiol. 2017 Mar;232(3):610-616. doi: 10.1002/jcp.25458. Epub 2016 Jun 30.
High molecular weight FGF2 transgenic mice (HMWTg) phenocopy the Hyp mouse, homolog of human X-linked hypophosphatemic rickets with phosphate wasting and abnormal fibroblast growth factor (FGF23), fibroblast growth factor receptor (FGFR), Klotho and mitogen activated protein kinases (MAPK) signaling in kidney. In this study, we assessed whether short-term (24 h) in vivo administration of FGF23 neutralizing antibody (FGF23Ab) could rescue hypophosphatemia and impaired FGFR signaling in kidneys of HMWTg male mice. Bone mineral density and bone mineral content in 1-month-old HMWTg mice were significantly reduced compared with Control/VectorTg mice. Serum FGF23 was significantly increased in HMWTg compared with VectorTg. Serum phosphate was significantly reduced in HMWTg and was rescued by FGF23Ab. Serum parathyroid hormone (PTH) was significantly increased in HMWTg but was not reduced by FGF23Ab. 1, 25(OH) D was inappropriately normal in serum of HMWTg and was significantly increased in both Vector and HMWTg by FGF23Ab. Analysis of HMWTg kidneys revealed significantly increased mRNA expression of the FGF23 co-receptor Klotho, transcription factor mRNAs for early growth response-1 transcription factor (Egr-1), and c-fos were all significantly decreased by FGF23Ab. A significant reduction in the phosphate transporter Npt2a mRNA was also observed in HMWTg kidneys, which was increased by FGF23Ab. FGF23Ab reduced p-FGFR1, p-FGFR3, KLOTHO, p-ERK1/2, C-FOS, and increased NPT2A protein in HMWTg kidneys. We conclude that FGF23 blockade rescued hypophosphatemia by regulating FGF23/FGFR downstream signaling in HMWTg kidneys. Furthermore, HMWFGF2 isoforms regulate PTH expression independent of FGF23/FGFR signaling. J. Cell. Physiol. 232: 610-616, 2017. © 2016 Wiley Periodicals, Inc.
高分子量FGF2转基因小鼠（HMWTg）表现出与Hyp小鼠相似的表型，Hyp小鼠是人类X连锁低磷血症佝偻病的同源物，伴有磷酸盐流失以及肾脏中异常的成纤维细胞生长因子（FGF23）、成纤维细胞生长因子受体（FGFR）、α-klotho和丝裂原活化蛋白激酶（MAPK）信号传导。在本研究中，我们评估了体内短期（24小时）给予FGF23中和抗体（FGF23Ab）是否能挽救HMWTg雄性小鼠肾脏中的低磷血症和受损的FGFR信号传导。与对照/载体转基因小鼠相比，1月龄HMWTg小鼠的骨密度和骨矿物质含量显著降低。与载体转基因小鼠相比，HMWTg小鼠血清FGF23显著升高。HMWTg小鼠血清磷酸盐显著降低，而FGF23Ab可使其恢复。HMWTg小鼠血清甲状旁腺激素（PTH）显著升高，但FGF23Ab并未使其降低。HMWTg小鼠血清中1,25(OH)D水平异常正常，FGF23Ab使载体转基因小鼠和HMWTg小鼠血清中的1,25(OH)D均显著升高。对HMWTg小鼠肾脏的分析显示，FGF23共受体α-klotho的mRNA表达显著增加，早期生长反应-1转录因子（Egr-1）和c-fos的转录因子mRNA均因FGF23Ab而显著降低。在HMWTg小鼠肾脏中还观察到磷酸盐转运体Npt2a mRNA显著减少，而FGF23Ab可使其增加。FGF23Ab降低了HMWTg小鼠肾脏中p-FGFR1、p-FGFR3、α-KLOTHO、p-ERK1/2、C-FOS的水平，并增加了NPT2A蛋白的水平。我们得出结论，FGF23阻断通过调节HMWTg小鼠肾脏中FGF23/FGFR下游信号传导挽救了低磷血症。此外，HMWFGF2亚型独立于FGF23/FGFR信号传导调节PTH表达。《细胞生理学杂志》232: 610 - 616, 2017。© 2016威利期刊公司
