DNA mismatch repair enzyme expression in synovial tissue
DNA mismatch repair enzyme expression in synovial tissue
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DOI：
10.1136/ard.2003.017210
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发表时间：
2004-12-01
影响因子：
27.4
通讯作者：
Firestein, GS
中科院分区：
文献类型：
--
作者：
Simelyte, E;Boyle, DL;Firestein, GS
背景：类风湿关节炎（RA）滑膜组织中的氧化应激可导致滑膜细胞DNA损伤并抑制DNA错配修复（MMR）系统。这种机制包括两种酶复合物，hMutSa（hMSH 2/hMSH 6）和hMutSbeta（hMSH 2/hMSH 3）。目的：研究MMR酶在关节炎患者和正常人滑膜组织中的表达和分布。方法：用抗hMSH 2，hMSH 3和hMSH 6的单克隆抗体对RA，骨关节炎（OA）患者或正常人的滑膜组织进行免疫组化分析。结果：hMSH 2、hMSH 3、hMSH 6在滑膜组织中均有表达，内膜中表达高于内膜下层。在RA和OA中，hMSH 6和hMSH 3的血管周围染色也很突出。hMSH 2、hMSH 3和hMSH 6在RA和OA滑膜下层的表达明显高于正常滑膜。免疫组化双标记结果显示，RA滑膜内膜层中主要表达MMR酶的细胞为CD 68（+）和CD 68（-）细胞。虽然MMR酶在RA中的表达高于正常组织，但这种代偿反应不能克服遗传毒性环境，DNA损伤会累积。
Background: Oxidative stress in RA synovial tissue can cause DNA damage and suppress the DNA mismatch repair (MMR) system in cultured synoviocytes. This mechanism includes two enzyme complexes, hMutSa (hMSH2/hMSH6) and hMutSbeta (hMSH2/hMSH3).Objective: To examine the expression and distribution of MMR enzymes in synovial tissues from patients with arthritis and from normal subjects.Methods: Synovial tissues from patients with RA, osteoarthritis (OA), or normal subjects were analysed by immunohistochemistry using monoclonal antibodies to hMSH2, hMSH3, and hMSH6. MMR protein expression was evaluated by computer assisted digital image analysis.Results: hMSH2, hMSH3, and hMSH6 were found in most synovial tissues evaluated, with greater levels in the intimal lining than sublining regions. In RA and OA, sublining perivascular staining for hMSH6 and hMSH3 was also prominent. Significantly higher sublining expression of hMSH2, hMSH3, and hMSH6 was seen in RA and OA than in normal synovium. Double label immunohistochemistry demonstrated that the main cells expressing MMR enzymes were CD68(+) and CD68(-) cells in the intimal lining.Conclusions: DNA MMR enzyme expression is greatest in the synovial intimal lining layer, where maximal oxidative stress in RA occurs. Although MMR enzyme expression is greater in RA than in normal tissue, this compensatory response cannot overcome the genotoxic environment, and DNA damage accumulates.