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

FGF和IGF在RA滑膜增生的发生和发展中起重要作用。我们最近证明了FGF 1直接与整合素αvβ3结合，并且整合素结合缺陷型FGF 1突变体（FGF α v β 50 E）不能诱导细胞增殖; IGF 1也是如此。在这里，我们研究了生长因子整合素的相互作用是如何参与生长因子信号转导。cDNA微阵列分析显示，与野生型FGF 1处理的细胞相比，FGF 1 R50 E处理的RA滑膜细胞中EGR-1 mRNA表达显著降低。RA滑膜细胞对FGF 1或IGF 1的反应是迅速诱导EGR-1 mRNA和蛋白的表达，但在FGF^R50 E或IGFR ^36 E/R37 E处理的滑膜细胞中，EGR-1的表达显著受损。siRNA下调EGR-1表达可促进H2 O2或依托泊苷处理的滑膜细胞凋亡。

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.