二氮嗪拮抗软骨氧化损伤的作用机制研究

Osteoarthritis (OA) is a degenerative arthritis, reduce the patient's quality of life and social productivity. Until now, there is no satisfactory therapeutic effect. Studies have shown oxidative damage plays a key role in the pathogenesis of OA, it is to reduce the intra-articular reactive oxygen species (ROS) generation and a new hot spot for the prevention and treatment of OA. Diazoxide is a mitochondrial ATP-sensitive potassium channel (mitoKATP channel) opener, which has antioxidant properties. Mobasheri finds out KATP channel exists in normal human articular chondrocytes and osteoarthritis chondrocytes. For the first time, our research confirmed mitoKATP channel opener to reduce hydrogen peroxide-induced OA chondrocytes apoptosis, reducing the generation of ROS, reversed OA chondrocytes hydrogen peroxide-induced decrease of type II collagen, initial validation of open mitoKATP channel can confront cartilage cells from oxidative injury and inhibiting the progress of the OA. This project intends to explore the best concentration and optimal dose in vitro and animal experiments diazoxide protective effect of OA and from the point of view of the open chondrocytes potassium channel reveals diazoxide mechanism of anti-oxidative damage and to provide new therapeutic targets for the clinical treatment of OA.

骨性关节炎（OA）是种降低患者的生活质量和社会生产力的退行性关节炎，目前尚无满意的治疗效果。研究证明氧化损伤在OA的发病机制中起关键作用，故降低关节腔内活性氧（ROS）的产生，是预防及治疗OA的一个新热点。二氮嗪是一种线粒体ATP敏感性钾通道（mitoKATP通道）开放剂，其具有抗氧化作用。Mobasheri A发现人正常软骨细胞及骨关节炎软骨细胞存在KATP通道。本课题组首次证实mitoKATP通道开放剂能降低双氧水诱导的OA软骨细胞的凋亡，降低ROS的产生，逆转双氧水诱导的OA软骨细胞二型胶原的降低，初步验证开放mtioKATP通道可对抗软骨细胞氧化损伤，抑制OA的进展，本项目进一步拟在体外实验和动物实验中探索最佳浓度和最佳剂量的二氮嗪对OA的保护作用及从开放软骨细胞钾通道的角度来揭示二氮嗪抗氧化损伤的机制，为临床治疗OA提供新的治疗靶点。

骨性关节炎（OA）是种降低患者的生活质量和社会生产力的退行性关节炎，目前尚无满意的治疗效果。研究证明内质网应激和细胞自噬在OA的发病机制中起关键作用，故抑制内质网应激和激活细胞自噬，是预防及治疗OA的一个新热点。二氮嗪是一种线粒体ATP敏感性钾通道（mitoKATP通道）开放剂，其具有抑制内质网应激和激活细胞自噬的作用。Mobasheri A发现人正常软骨细胞及骨关节炎软骨细胞存在KATP通道。本课题组通过细胞和动物实验证实，二氮嗪能够通过抑制内质网应激通路和激活细胞自噬通路，调节骨关节炎相关的生物标记物，从而减少软骨细胞的凋亡和关节软骨的退行性变。我们的实验结果表明，二氮嗪是一种十分具有潜力的预防和治疗骨性关节炎的药物。