Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice
Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice
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DOI：
10.1136/ard.2010.132720
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发表时间：
2011-05-01
影响因子：
27.4
通讯作者：
Pufe, Thomas
中科院分区：
文献类型：
--
作者：
Wruck, Christoph Jan;Fragoulis, Athanassios;Pufe, Thomas
目的越来越多的证据表明，氧化应激可能在类风湿关节炎（RA）关节破坏中起关键作用。本研究的目的是阐明核因子红细胞2相关因子2（Nrf 2），一种转录因子，维持细胞防御氧化应激，在RA的作用。方法Nrf 2的激活状态进行了评估，从RA患者的滑膜组织中使用免疫组化。在Nrf 2敲除小鼠和Nrf 2野生型对照小鼠中诱导抗体诱导的关节炎（AIA）。使用损伤评分评价软骨破坏的严重程度。通过免疫组织化学染色分析氧化应激的程度、Nrf 2的活化状态和Nrf 2靶基因的表达水平。使用Luminex技术检测血管内皮生长因子（VEGF）-A的mRNA和蛋白质表达。采用Xenogen成像系统检测抗氧化反应元件-荧光素酶转基因小鼠AIA过程中Nrf 2的活性。Nrf 2基因敲除小鼠有更严重的软骨损伤和更多的氧化损伤，Nrf 2靶基因的表达在Nrf 2野生型中增强，但在AIA期间敲除小鼠中没有增强。在AIA过程中，Nrf 2基因敲除小鼠的VEGF-A mRNA和蛋白表达均上调。一个意想不到的发现是Nrf 2基因敲除小鼠与AIA.Conclusion自发骨折的骨的数量提供了强有力的证据，氧化应激显着参与实验性关节炎的软骨降解，并表明，功能性Nrf 2基因的存在是限制软骨破坏的主要要求。
Objectives Increasing evidence suggests that oxidative stress may play a key role in joint destruction due to rheumatoid arthritis (RA). The aim of this study was to elucidate the role of nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that maintains the cellular defence against oxidative stress, in RA.Methods The activation status of Nrf2 was assessed in synovial tissue from patients with RA using immunohistochemistry. Antibody-induced arthritis (AIA) was induced in Nrf2-knockout and Nrf2-wild-type control mice. The severity of cartilage destruction was evaluated using a damage score. The extent of oxidative stress, the activation state of Nrf2 and the expression level of Nrf2 target genes were analysed by immunhistological staining. The expression of vascular endothelial growth factor (VEGF)-A was examined on mRNA and protein using the Luminex technique. A Xenogen imaging system was used to measure Nrf2 activity in an antioxidant response element-luciferase transgenic mouse during AIA.Results Nrf2 was activated in the joints of arthritic mice and of patients with RA. Nrf2-knockout mice had more severe cartilage injuries and more oxidative damage, and the expression of Nrf2 target genes was enhanced in Nrf2-wild-type but not in knockout mice during AIA. Both VEGF-A mRNA and protein expression was upregulated in Nrf2-knockout mice during AIA. An unexpected finding was the number of spontaneously fractured bones in Nrf2-knockout mice with AIA.Conclusion These results provide strong evidence that oxidative stress is significantly involved in cartilage degradation in experimental arthritis, and indicate that the presence of a functional Nrf2 gene is a major requirement for limiting cartilage destruction.