HMGB-1影响局部MSC的特性是实验性类风湿性关节炎发病的重要环节

项目名称： HMGB-1影响局部MSC的特性是实验性类风湿性关节炎发病的重要环节

项目编号： No.30871018

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 金属学与金属工艺

项目作者： 郭子宽

作者单位： 中国人民解放军军事医学科学院

项目金额： 30万元

中文摘要： 类风湿性关节炎（RA）是一种以骨和关节损伤为主要病变的自身免疫性疾病；其中，肿瘤坏死因子（TNF-alpha）和高迁徙组蛋白-1（HMGB-1）是RA发病的重要因子。间充质干细胞（MSC）是骨、软骨和脂肪组织的干细胞，而且，MSC具有很强的免疫调节作用。因此，课题组探讨了HMGB-1和TNF-alpha处理后，MSC体外免疫调节能力，并利用经典的大鼠RA模型，观察MSC对RA的治疗作用及其机制。结果表明：（1）HMGB-1能促进MSC的迁徙，抑制MSC增殖并诱导其成骨分化；（2）HMGB-1处理后，MSC免疫调节能力未发生改变；（3）TNF-alpha处理后，MSC细胞内NF-kappa B转录因子向核内转移，而且，处理的细胞有更强的混合淋巴细胞反应抑制作用；（4）然而，CIA大鼠接受MSC、TNF-alpha处理的MSC或者MSC裂解物后，大鼠关节炎症状、病理改变和X-线改变，均较未治疗组加重；（5）甲氨蝶呤和HMGB-1的封闭剂A-box则显示明确的治疗作用。研究新发现：（1）应慎重考虑使用MSC治疗RA；（2）A-box具有潜在的RA治疗价值。

中文关键词： 类风湿性关节炎；间充质干细胞；高迁徙组蛋白-1

英文摘要： Rheumatoid arthritis (RA) is an autoimmune disease characterized by the destruction of the invovled bones and joints. It is generally accepted now that tumor necrosis factor-alpha (TNF-αand high mobility group protein-1 (HMGB-1) play en essential role in the developmental process of RA. Mesenchymal stem cells (MSC) are an adult stem cells with ability to form bone, cartilage and adipose tissues. Moreover, MSC have potent immuno-regulatory activity. Based on herein, the immmunomodulatory effects of MSC and HMGB-1- and TNF-αreated MSC were investigated in this study in vitro and in a rat RA model. The results showed that HMGB-1 could promote the migration of MSC, inhibit their proliferation and enhance MSC differentiation along osteoblastic pathway, though HMGB-1 treatment had little effect on their immunoregulatory activity. Further, TNF-αreatment resulted in the translocation of NF-kappa B into the nuclei of MSC, and enhanced their inhibitory activity on mixed lymphocyte reaction aroused by splenocytes from SD and Wistar rats. However, the symptoms, pathological and X-ray changes of the arthtitis joints were aggreviated in a rat model of collagen-induced arthritis after the rats received MSC, TNF-αreated MSC or MSC lysates. Methotrexate and A-box, a blocker of HMGB-1, exhibited obvious therapeutic activity on rat arthritis. It is concluded that in sharp contrast with the immune regulation function of MSC in vitro, MSC treatment has no benificial effect on RA, and the difference might be attributed to the persistence of HMGB-1 and TNF-alpha. Further, the results here suggest that it should be prudent to perform MSC therapy in RA and A-box might be a potential agent for RA treatment.

英文关键词： mesenchymal stem cells; rheumatoid arthritis; HMBG-1