Inhibition of epidermal growth factor receptor tyrosine kinase ameliorates collagen-induced arthritis.
Inhibition of epidermal growth factor receptor tyrosine kinase ameliorates collagen-induced arthritis.
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DOI：
10.4049/jimmunol.1102693
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发表时间：
2012-04-01
期刊：
影响因子：
--
通讯作者：
Robinson WH
中科院分区：
文献类型：
--
作者：
Swanson CD;Akama-Garren EH;Stein EA;Petralia JD;Ruiz PJ;Edalati A;Lindstrom TM;Robinson WH
类风湿性关节炎（RA）是一种自身免疫性滑膜炎，其特征是滑膜关节形成和软骨和骨的破坏。虽然免疫细胞在RA的发病机制中起着突出的作用，但其他细胞类型也有贡献。例如，滑膜成纤维细胞的增殖是输卵管形成的基础，而内皮细胞的增殖导致新生血管形成，通过为输卵管提供营养和氧气来支持其生长。滑膜成纤维细胞也通过产生细胞因子和趋化因子促进滑膜炎症。最后，破骨细胞会破坏骨骼。在这里，我们展示了厄洛替尼，一种酪氨酸激酶EGFR的抑制剂，降低了已建立的胶原诱导关节炎（CIA）的严重程度，这是一种ra的小鼠模型，它是通过靶向滑膜成纤维细胞、内皮细胞和破骨细胞来实现的。厄洛替尼诱导的自身免疫性关节炎的衰减与破骨细胞和血管数量的减少有关，厄洛替尼在体外抑制小鼠破骨细胞的形成和人内皮细胞的增殖。厄洛替尼还能抑制体外滑膜成纤维细胞的增殖和细胞因子的产生。此外，EGFR在CIA小鼠和RA患者的滑膜中高表达和激活。总之，这些发现表明EGFR在RA的发病机制中起着核心作用，抑制EGFR可能对RA的治疗有益。
Rheumatoid arthritis (RA) is an autoimmune synovitis characterized by the formation of pannus and the destruction of cartilage and bone in the synovial joints. Although immune cells, which infiltrate the pannus and promote inflammation, play a prominent role in the pathogenesis of RA, other cell types also contribute. Proliferation of synovial fibroblasts, for example, underlies the formation of the pannus, while proliferation of endothelial cells results in neovascularization, which supports the growth of the pannus by supplying it with nutrients and oxygen. The synovial fibroblasts also promote inflammation in the synovium by producing cytokines and chemokines. Finally, osteoclasts cause the destruction of bone. Here we show that erlotinib, an inhibitor of the tyrosine kinase EGFR, reduces the severity of established collagen-induced arthritis (CIA), a mouse model of RA—and that it does so by targeting synovial fibroblasts, endothelial cells, and osteoclasts. Erlotinib-induced attenuation of autoimmune arthritis was associated with a reduction in number of osteoclasts and blood vessels, and erlotinib inhibited the formation of murine osteoclasts and the proliferation of human endothelial cells in vitro. Erlotinib also inhibited the proliferation and cytokine production of human synovial fibroblasts in vitro. Moreover, EGFR was highly expressed and activated in the synovium of mice with CIA and patients with RA. Together, these findings suggest that EGFR plays a central role in the pathogenesis of RA and that EGFR inhibition may provide benefit in the treatment of RA.
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影响因子：
6.7
作者：
Lu, Jian-Feng;Eppler, Steve M.;Lum, Bert L.
通讯作者：
Lum, Bert L.
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2.1
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1.8
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