Development of a novel therapeutic method for rheumatoid arthritis by targeting growth factor signaling

成纤维细胞生长因子和胰岛素样生长因子在类风湿关节炎滑膜增生症的发生发展中起重要作用。我们最近证实，FGF1直接与整合素αvβ3结合，而整合素结合缺陷的FGF1突变体(FGF^R50E)不能诱导细胞增殖；IGF1也是如此。在这里，我们研究了生长因子-整合素相互作用如何参与生长因子信号转导。基因芯片分析显示，与野生型FGF1处理的RA滑膜细胞相比，经成纤维细胞生长因子、R50E处理的RA滑膜细胞中EGR-1mRNA的表达显著降低。FGF1或IGF1能迅速诱导RA滑膜细胞中EGR-1mRNA和蛋白的表达，但在FGF1、R50E或IGFR+36E/R37E处理的滑膜细胞中，EGR-1的表达明显减弱。SiRNA下调EGR-1的表达有助于H_2O_2或依托泊苷诱导的滑膜细胞的凋亡。

FGF and IGF are of interest in the initiation and development of RA synovial hyperplasia. We recently demonstrated that FGF1 binds directly to integrin αvβ3, and that an integrin-binding-defective FGF1 mutant (FGF^R50E) cannot induce cell proliferation; this is also true for IGF1. Here we investigated how the growth factor-integrin interaction is involved in growth factor signaling. The cDNA microarray analysis showed markedly reduced EGR-1 mRNA expression in the FGF^R50E-treated RA synoviocytes, compared to wild-type FGF1-treated cells. EGR-1 mRNA and protein were rapidly induced in RA synoviocytes in response to FGF1 or IGF1, but the EGR-1 expression was significantly impaired in FGF^R50E-or IGFR^36E/R37E-treated synoviocytes. The down-regulation of EGR-1 by siRNA facilitated the apoptosis of synoviocytes treated with H2O2 or etoposide.