IL-1和TNF-α拮抗剂治疗骨关节炎实验研究  

Effect of Both IL-1 and TNF-α Blockade for Experimental Osteoarthritis

作　　者：王海军[1] 于长隆[1] 岸裕幸 村口笃 毛泽斌[3] 傅欣[1] 张继英[1] 张智清[4] 

机构地区：[1]北京大学第三医院运动医学研究所 [2]日本富山大学医学院免疫学系 [3]北京大学医学部生物化学与分子生物学系 [4]中国疾病预防控制中心病毒学研究所

出　　处：《中国运动医学杂志》2006年第5期551-555,共5页Chinese Journal of Sports Medicine

摘　　要：目的:观察腺病毒载体介导的白细胞介素1受体拮抗蛋白(IL-1Ra)和可溶性肿瘤坏死因子Ⅰ型受体(sTNF-RI)基因转移对兔骨关节炎的治疗作用,并探讨IL-1和TNF-α在骨关节炎发生中的作用。方法:构建Ad-IL-1Ra和Ad-sTNF-RI腺病毒载体,注射到兔骨性关节炎膝关节腔内。关节内注射腺病毒后第3天和第7天,分别用1ml生理盐水灌洗膝关节,抽取关节腔灌注液采用ELISA分析外源基因的表达。第7天处死动物,取膝关节股骨内侧髁软骨和滑膜常规石蜡切片,软骨HE染色、甲苯胺蓝染色和滑膜组织HE染色检查病理改变,并进行软骨组织学评分。结果:膝关节内注射IL-1Ra能明显抑制关节软骨的破坏,但对滑膜炎无明显治疗作用;单独sTNF-RI基因治疗对关节软骨的破坏和滑膜炎均无明显的作用。结论:IL-1Ra对骨关节炎关节软骨有明显的保护作用,而sTNF-RI对骨关节炎无明显的治疗作用,这提示在骨关节炎的发生中IL-1可能起主要的作用,因而抑制IL-1的作用对骨关节炎的治疗更为有效。Objective To determine the efficacy of local expression of interlukin - 1 receptor antagonist （IL- 1Ra） and soluble tumor necrosis factor- α receptor type Ⅰ （sTNF- RI） by direct adenoviral- mediated intra- articular gene delivery in the rabbit model of osteoarthritis and to investigate the relative importance of IL - 1 and TNF - α in the pathophysiology of osteoarthritis. Methods Adenoviral vectors containing IL - 1 Ra or sTNF - RI genes were constructed and then injected into the joint space of the rabbit osteoarthritis knee. Three days after injection of the adenovirus, both knees of each rabbit were lavaged with 1 ml of saline solution. At day 7, the rabbits were sacrificed, and the knees were lavaged, dissected and analyzed for effects of transgene expression. Levels of IL- 1Ra and sTNF - RI expression in recovered lavage fluids were measured using a cytokine ELISA kit. Cartilage from the lesion areas of medial femoral condyle and synovium were fixed, embedded, sectioned and stained with hematoxylin and eosin （cartilage and synovium） and toluidine blue （cartilage）. The samples were examined by light microscopy and quantitatively evaluated. Results Intra - articular delivery of IL - 1 Ra resulted in a significant inhibition of cartilage degradation, but did not affect synovial changes. In contrast, rabbit knee joints receiving sTNF - RI alone showed no detectable reduction in cartilage degradation and synovial inflammation. Conclusion These results show that IL- 1 Ra has good chondroprotective properties, but TNF- α blockade has little therapeutic effect on osteoarthritis, suggesting IL- 1 may play a more important role in the pathogenesis of osteoarthritis than TNF - α and so inhibition of IL - 1 may be more efficacious in treating osteoarthritis.

关 键 词：基因治疗 骨性关节炎 IL-1RA sTNF—RI 腺病毒载体 

分 类 号：R684.3[医药卫生—骨科学]