Transcription Factor Snail Regulates Tumor Necrosis Factor α-Mediated Synovial Fibroblast Activation in the Rheumatoid Joint
Transcription Factor Snail Regulates Tumor Necrosis Factor α-Mediated Synovial Fibroblast Activation in the Rheumatoid Joint
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DOI：
10.1002/art.38899
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发表时间：
2015-01-01
影响因子：
13.3
通讯作者：
Wang, Chrong-Reen
中科院分区：
文献类型：
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作者：
Chen, Shih-Yao;Shiau, Ai-Li;Wang, Chrong-Reen
Objective.转录因子Snail参与多种生物学功能。我们假设这种分子调节类风湿关节中肿瘤坏死因子α（TNF α）介导的滑膜成纤维细胞活化。本研究的目的是检测Snail在钙粘蛋白-11（Cad-11）和肌成纤维细胞标志物表达、白细胞介素-6（IL-6）产生以及细胞侵袭能力中的作用。滑膜样品从患有类风湿性关节炎（RA）的患者和患有胶原诱导的关节炎（CIA）的大鼠获得。滑膜成纤维细胞用TNF α或Wnt信号诱导剂处理，CIA大鼠关节注射TNF α拮抗剂。通过慢病毒载体介导的互补DNA或短发夹RNA的转移来调节滑膜成纤维细胞和关节中Snail的表达。与骨关节炎患者相比，RA患者滑膜和滑膜成纤维细胞中Snail和Cad-11的表达更高，CIA大鼠中Snail和Cad-11的表达增加。TNF α刺激或Wnt信号的激活上调滑膜成纤维细胞中Snail、Cad-11和α-平滑肌肌动蛋白（α-SMA）的表达，抗TNF α治疗下调CIA大鼠关节中Snail、Cad-11和α-SMA的表达。尽管Snail过表达的滑膜成纤维细胞转染子显示Cad-11和α-SMA表达增加，TNF α介导的侵袭能力和IL-6产生增强，但来自CIA大鼠的Snail沉默的滑膜成纤维细胞转染子显示表达降低，对这些功能具有相反的作用。Snail过度表达的正常关节具有增生的滑膜，Cad-11、α-SMA和IL-6的表达增加。沉默Snail表达可改善CIA大鼠关节炎，降低Cad-11表达，减少关节内细胞外基质沉积水平，而过度表达Snail可加重关节炎，增加Cad-11表达，增加细胞外基质沉积水平。我们的研究结果表明，蜗牛调节TNF α介导的激活滑膜成纤维细胞在类风湿关节。这些发现可能有助于RA患者滑膜成纤维细胞靶向治疗的药理学发展。
Objective. The transcription factor Snail is involved in various biologic functions. We hypothesized that this molecule regulates tumor necrosis factor alpha (TNF alpha)-mediated synovial fibroblast activation in the rheumatoid joint. The aim of this study was to examine the role of Snail in the expression of cadherin-11 (Cad-11) and myofibroblast markers, interleukin-6 (IL-6) production, and the invasive ability of cells.Methods. Synovium samples were obtained from patients with rheumatoid arthritis (RA) and from rats with collagen-induced arthritis (CIA). Synovial fibroblasts were treated with TNF alpha or a Wnt signaling inducer, and the joints of rats with CIA were injected with a TNF alpha antagonist. Modulation of Snail expression in the synovial fibroblasts and joints was performed by lentiviral vector-mediated transfer of complementary DNA or short hairpin RNA.Results. The expression of Snail and Cad-11 was higher in synovium and synovial fibroblasts from patients with RA compared with patients with osteoarthritis and was increased in rats with CIA. TNF alpha stimulation or activation of Wnt signaling up-regulated the expression of Snail, Cad-11, and alpha-smooth muscle actin (alpha-SMA) in synovial fibroblasts, and anti-TNF alpha therapy down-regulated the expression of Snail, Cad-11, and alpha-SMA in the joints of rats with CIA. Although synovial fibroblast transfectants in which Snail was overexpressed showed increased expression of Cad-11 and alpha-SMA and enhanced TNF alpha-mediated invasive capacity and IL-6 production, synovial fibroblast transfectants from rats with CIA in which Snail was silenced showed decreased expression and had the opposite effect on these functions. Normal joints in which Snail was overexpressed had hyperplastic synovium, with increased expression of Cad-11, alpha-SMA, and IL-6. Silencing Snail expression ameliorated arthritis, with reduced Cad-11 expression and reduced levels of extracellular matrix deposition in the joints of rats with CIA, whereas overexpression of Snail exacerbated arthritis, with increased Cad-11 expression and increased levels of extracellular matrix deposition.Conclusion. Our results demonstrate that Snail regulates TNF alpha-mediated activation of synovial fibroblasts in the rheumatoid joint. These findings may contribute to the pharmacologic development of therapeutics targeting synovial fibroblasts in patients with RA.