Etanercept抑制BNX鼠-人RA移植物嵌合体模型中的滑膜增生和软骨侵蚀及降解  

The suppression of synovial hyperplasia, cartilage invasion and degradation in the chimera model of BNX mice - human rheumatoid arthritis grafts by etanercept

作　　者：肖长虹[1] 顾为望[2] 张嘉宁[2] 马剑颖[1] 黄世峰[2] 杨敏[1] 陈德超[1] 

机构地区：[1]南方医科大学中医药学院风湿病科,广州510515 [2]南方医科大学实验动物中心

出　　处：《中华风湿病学杂志》2008年第1期12-16,74,共6页Chinese Journal of Rheumatology

基　　金：广东省科技攻关计划基金资助项目（2004860301007）

摘　　要：目的观察肿瘤坏死因子（TNF）-α拮抗剂Etanercept能否抑制类风湿关节炎（RA）的滑膜增生和软骨破坏，并探讨作用机制。方法将人RA滑膜和正常关节软骨移植到BNX小鼠皮下构建BNX鼠-人RA移植物嵌合体模型，造模4周后给予Etanercept（100μg）皮下注射，连续4周，对照组给予注射用水。评价移植物中的滑膜增生、滑膜细胞对软骨的侵蚀和软骨细胞周围软骨降解的组织学积分，并检测血清TNF-α含量，滑膜的TNF-α和人血管内皮生长因子（VEGF）的表达以及滑膜细胞凋亡情况。结果与对照组比较．Etanercept组中滑膜增生、软骨侵蚀、软骨降解积分以及血清TNF-α含量均显著降低：滑膜细胞的TNF-α和VEGF表达水平也显著下降。但滑膜细胞凋亡程度差异无统计学意义。结论Etanercept能抑制嵌合体模型中的滑膜增生和软骨侵蚀及降解。其作用机制除了中和滑膜组织和血液中的TNF-α外．还可能与下调滑膜细胞的VEGF表达有关。Objective To investigate the suppression of synovial hyperplasia and cartilage destruction in rheumatoid arthritis by Etanereept-the TNF-α-blocking agent, and its pharmacological mechanism is explored. Methods The synovium from patients with RA and normal articular cartilage were co-implanted into the back of BNX mice to set up a chimera model of BNX-HuRAg. Four weeks later after the implantation, the mice were treated with Etanercept （100μg） and distilled water （as control） subcutaneously twice a week, for 4 weeks respectively. The histological scores of grafts on synovial hyperplasia, cartilage invasion by synoviocytes and perichondrocytic cartilage degradation were evaluated, and the serum level of TNF-α was detected with radioimmunoassay. The expression of TNF-α mRNA and VEGF mRNA in synovium were detected with ISH, the apoptosis in the synovium was detected with TUNEL, and the results were analyzed by image analysis system. Results The grafts kept live in the mice till the end of this study. In the etanercept treatment group, the scores of synovial hyperplasia （2.1 ± 1.1 vs 3.7±0.5）, cartilage invasion （ 1.6±0.6 vs 2.6±1.1 ）, cartilage degradation （2.7±0.9 vs 1.3±0.5） and the serum level of TNF-α （0.60±0.10 vs 0.69±0.11, ng/ml） decreased significantly while the expressions of TNF-α and VEGF in the synovium declined significantly. But the apoptosis in synovium did not show significant difference between Etanercept and control groups. Conclusion Etanercept is effective in suppressing the synovial hyperplasia and the cartilage invasion and degradation in the BNX-HuRAg model. The pharmacological mechanism that it can not only neutralize the TNF-α in the synovium and blood, but also down regulates the expression of VEGF in synovium.

关 键 词：关节炎 类风湿 滑膜 软骨 ETANERCEPT BNX鼠 

分 类 号：R593.22[医药卫生—内科学]