Simelyte E, Boyle D L, Firestein G S
Division of Rheumatology, Allergy, and Immunology, School of Medicine, University of California at San Diego, La Jolla 92093-0656, USA.
Ann Rheum Dis. 2004 Dec;63(12):1695-9. doi: 10.1136/ard.2003.017210.
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, hMutSalpha (hMSH2/hMSH6) and hMutSbeta (hMSH2/hMSH3).
To examine the expression and distribution of MMR enzymes in synovial tissues from patients with arthritis and from normal subjects.
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.
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.
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.
类风湿关节炎（RA）滑膜组织中的氧化应激可导致DNA损伤，并抑制培养的滑膜细胞中的DNA错配修复（MMR）系统。该机制包括两种酶复合物，即hMutSα（hMSH2/hMSH6）和hMutSβ（hMSH2/hMSH3）。
检测关节炎患者和正常受试者滑膜组织中MMR酶的表达及分布情况。
采用针对hMSH2、hMSH3和hMSH6的单克隆抗体，通过免疫组织化学方法分析RA、骨关节炎（OA）患者或正常受试者的滑膜组织。采用计算机辅助数字图像分析评估MMR蛋白表达。
在所评估的大多数滑膜组织中均发现hMSH2、hMSH3和hMSH6，在内皮层中的水平高于内膜下层区域。在RA和OA中，内膜下层血管周围hMSH6和hMSH3的染色也很明显。RA和OA中hMSH2、hMSH3和hMSH6的内膜下层表达明显高于正常滑膜。双重免疫组织化学显示，表达MMR酶的主要细胞是内膜层中的CD68(+)和CD68(-)细胞。
DNA错配修复酶的表达在滑膜内膜层最高，而RA中最大的氧化应激就发生在此处。虽然RA中MMR酶的表达高于正常组织，但这种代偿反应无法克服基因毒性环境，DNA损伤会不断累积。
