软骨蛋白聚糖诱导的脊柱关节炎小鼠模型的建立及富含半胱氨酸蛋白61单克隆抗体治疗效应初探  

A proteoglycan-induced spondyloarthritis mouse model and the therapeutic effect of CCN1 monoclonal antibody

作　　者：李佳洁 李会丹[2] 张洁[2] 翟天航 火蓉芬[2] 沈佰华[2] 信维伟[3] 李挺[1] 叶霜[1] 李宁丽[2] Li Jiajie;Li Huidan;Zhang Jie;Zhai Tianhang;Huo Rongfen;Shen Baihua;Xin Weiwei;Li Ting;Ye Shuang;Li Ningli(Department of Rheumatology, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201112, China;Shanghai Institute of Immunology and Department of Immunology and Microbiology, Shanghai 200025, China;Department of Orthopedics, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201112, China)

机构地区：[1]上海交通大学医学院附属仁济医院南院风湿科,201112 [2]上海市免疫学研究所,200025 [3]上海交通大学医学院附属仁济医院南院骨科,201112

出　　处：《中华风湿病学杂志》2019年第8期513-517,I0003,共6页Chinese Journal of Rheumatology

摘　　要：目的尝试建立SpA的小鼠模型,分析小鼠的临床表型及影像学和病理学特征。并初步探讨富含半胱氨酸蛋白61(CCN1)在SpA小鼠模型中的治疗作用。方法牛软骨蛋白聚糖和弗氏佐剂免疫14~16周龄雌性BALB/c小鼠,诱导SpA。SpA小鼠腹腔注射CCN1单克隆抗体093G9或者无关抗体免疫球蛋白(Ig)G。对小鼠外周关节炎进行评分,采用t检验进行统计分析,分析其外周及中轴关节Mirco-CT和组织病理学表现。结果免疫后小鼠从第8周陆续出现外周关节炎症,这一表现在第11周达到高峰[关节炎评分(10.5±1.5)]。第12周踝、膝关节骨赘形成,腰、尾椎椎间盘炎,膝关节半月板和腰椎椎间盘软骨细胞聚集。第18周胸、颈椎也出现椎间盘炎,伴软骨生成。2次CCN1单克隆抗体093G9治疗后的SpA小鼠外周关节炎评分明显下降,治疗组及正常对照组分别为[(2.8±1.3)和(4.2±2.1),t=2.516,P<0.05]。8次治疗后2组关节炎评分差异有统计学意义,治疗组为(2.0±2.0),而正常对照组为(5.3±2.0)(t=4.082,P<0.01)。治疗组外周关节炎症减轻,新骨形成减少,中轴关节椎间隙狭窄和新骨形成改善。结论本研究建立的SpA小鼠模型可以基本模拟人类SpA,包括外周、中轴炎症及新骨形成。CCN1单克隆抗体可改善SpA小鼠模型的炎症和新骨形成。Objective To set up a mouse model of spondyloarthritis, analyzethe clinical phenotype, radiographic and pathological features, and investigate the therapeutic effect of cysteine-rich 61 (CCN1) monoclonal antibody in spondyloarthritis mouse model. Methods Proteoglycan from bovine nasal septum was used for immunization of 14-16 week old female BALB/c mice. CCN1 monoclonal antibody 093G9 or control immunoglobulin (Ig)G were injected to the spondyloarthritis mice. The arthritis scores were analyzed by t test. Peripheral and axial joints disease development was assessed by Micro-CT and histology. Results Proteoglycan immunized mice began to develop peripheral arthritis in the 8th week. The peripheral arthritis score reached the peak (10.5±1.5) in the 11th week, with the inflammation and spur formation of the ankle and knee joint. We found infiltration of inflammation cells in intervertebral discs of the lumbar vertebrae and the caudal vertebrae. Chondrocyte proliferation couldbe seen in the meniscus of knee and lumbar intervertebral discs. In the 18th week, the intervertebral discsof thoracic vertebrae and the cervical vertebrae were also damaged. Abundant chondrocytesgathered in the intervertebral discs. The inflammation and new bone for-mation of peripheral and axial joints were more severe in control IgG group than 093G9 group. The peripheral arthritis score in the 093G9 group decreased significantly after 2 treatments,[(2.8±1.3) vs (4.2±2.1), t=2.516, P<0.05]. The difference in arthritis scores between the two groups was the most significant after 8 treatments,[(2.0±2.0) vs (5.3±2.0), t=4.082, P<0.01]. Conclusion The mouse model of spondyloarthritissimulates human spondylo-arthritis, including inflammation and new bone formation in peripheral and axial joints. CCN1 monoclonal antibody can improve the inflammation and new bone formation inspondyloarthritis mouse model.

关 键 词：脊柱炎 疾病 模型 动物 炎症 骨生成 

分 类 号：R593.23[医药卫生—内科学] R-332[医药卫生—临床医学]