ATDC5来源外泌体包载小分子药物5Z-7-Oxozeaenol治疗骨关节炎  

5Z-7-Oxozeaenol Delivered by ATDC5-derived Exosomes for the Treatment of Osteoarthritis

作　　者：樊逸菲 程锦[1] 徐雁[1] 何通川 敖英芳[1] 胡晓青[1] FAN Yi-Fei;CHENG Jin;XU Yan;HE Tong-Chuan;AO Ying-Fang;HU Xiao-Qing(Department of Sports Medicine,Peking University Third Hospital,Institute of Sports Medicine of Peking University,Beijing Key Laboratory of Sports Injuries,Beijing 100191,China;Department of Orthopaedic Surgery and Rehabilitation Medicine,The University of Chicago Medical Center,Chicago,IL 60637,USA)

机构地区：[1]北京大学第三医院运动医学科,北京大学运动医学研究所运动医学关节伤病北京市重点实验室,北京100191 [2]Department of Orthopaedic Surgery and Rehabilitation Medicine,The University of Chicago Medical Center,Chicago,IL 60637,USA

出　　处：《中国生物化学与分子生物学报》2023年第5期706-714,共9页Chinese Journal of Biochemistry and Molecular Biology

基　　金：国家自然科学基金项目(No.82072486)资助。

摘　　要：骨关节炎(osteoarthritis,OA)是一种常见的退行性关节疾病。研究表明,TAK1的抑制剂小分子药物5Z-7-Oxozeaenol(5Z-7),用于治疗OA时直接将药物进行频繁关节腔注射,药物的治疗效果有限。本研究选取小鼠胚胎瘤成软骨细胞系(ATDC5),是一种理想的成软骨细胞模型,其增殖速度和培养稳定性均优于间充质干细胞,用于提取外泌体作为药物的载体。本研究提取ATDC5来源的外泌体(ATDC5-Exos),包载药物5Z-7。在炎性细胞因子诱导大鼠软骨细胞模型中,载药外泌体可以促进合成代谢相关基因Col2a1、Sox9的表达,抑制分解代谢相关基因Adamts5、Mmp13的表达。本研究使用8周龄雄性小鼠,行前交叉韧带离断术(ACLT)诱导OA小鼠模型,关节腔注射外泌体或载药外泌体治疗,取膝关节石蜡切片进行组织学评估。结果显示,载药外泌体可缓解创伤后OA模型的病理表型。结合Micro-CT影像学结果显示,治疗能改善ACLT术后膝关节软骨下骨骨小梁的流失和骨赘减少,关节表面更为光滑。本研究证实,ATDC5-Exos包载药物5Z-7在体内和体外实验中均可缓解OA表型。外泌体包载递送5Z-7减少了药物的用量和给药频率,且药物和外泌体可以叠加治疗改善OA的效果。Osteoarthritis(OA)is a common degenerative disease.Previous studies have shown that the small molecule drug 5Z-7-Oxozeaenol(5Z-7),an inhibitor of TAK1,has a good effect on OA.5Z-7 has been directly injected into the joint cavity frequently,and the therapeutic effect of the drug is impaired.In this study,exosomes were isolated and purified from the cell supernatant of the ATDC5 cell line,which is an ideal chondrogenic model in vitro.In rat chondrocytes induced by proinflammatory cytokines,5Z-7-loaded exosomes can promote the expression of anabolism-related genes Col2a1 and Sox9,and inhibit the expression of catabolism-related genes Adamts5 and Mmp13.In this study,the OA model was established in 8-week-old male mice by anterior cruciate ligament transection(ACLT).In order to explore the therapeutic effect of exosomes,paraffin sections of knee joints were taken for histological evaluation after being treated with intra-articular injection of exosomes or 5Z-7-loaded exosomes.The results showed that drug-loaded exosomes could alleviate the pathological phenotypes of post-traumatic OA models.Combined with the results of Micro-CT,the treatment improved the loss of subchondral bone trabeculae,reduced osteophytes,and rendered the articular surface smoother after ACLT.This study confirmed that the ATDC5-derived and 5Z-7-loaded exosomes could alleviate the osteoarthritis phenotype in vivo and in vitro.The delivery of 5Z-7 in exosomes reduces the dosage and frequency of administration,and the loading of 5Z-7 can be superimposed onto the therapeutic effect of exosomes.

关 键 词：骨关节炎 5Z-7-Oxozeaenol 小分子药物 外泌体 

分 类 号：R684.3[医药卫生—骨科学]