内质网应激诱导的软骨细胞自噬和凋亡在骨关节炎发病中作用的研究

Osteoarthritis (OA) is one of the most important factors which affected the overall quality of life of millions of patients worldwide. At present, the pathogenesis of osteoarthritis is not very clear and lack of effective medical therapies. Chondrocytes, which play a very important role in cartilage metabolism, are the only cellular component of articular cartilage. The loss of chondrocytes is one of the most important pathological characters of OA. The apoptosis is the main factor which resultes in the loss of chondrocytes. The apoptosis induced by endoplasmic reticulum stress (ER stress) is a newly signal pathway of apoptosis in recent years. The autophagy induced by ER stress has a close relationship with apoptosis. But the roles of ER stress, chondrocytes autophagy and apoptosis have not been reported in the pathogenesis of OA. Our previous studies showed that the expression of proteins related with ER stress are higher in the articular cartilage of OA patients than those of controls. In the present study, in order to define the roles of autophagy and apoptosis which is induced by ER stress in the pathogenesis of OA, the effects of ER stress on the autophagy and apoptosis of chondrocytes will be observed on in vitro experiments and in vivo OA animal model. The apoptosis of chondrocytes after inhibition of autophagy will also be investigated on in vitro experiments. We will observe the expression of proteins which are related with ER stress and the markers of autophagy in the articular cartilage of OA patients to make sure the relationships of ER stress, autophagy and apoptsis in the pathogenesis of OA.

骨关节炎（OA）是引起老年人生活质量下降的主要原因之一，但OA的发病机理至今仍未明确，目前缺乏有效的防治手段。软骨细胞是关节软骨中的唯一细胞成份，在软骨代谢中起着关键作用。凋亡引起的软骨细胞减少是OA最主要的病理表现之一。内质网应激介导的细胞凋亡是一种新发现的细胞凋亡信号通路，而内质网应激引起的细胞自噬与细胞凋亡密切相关。内质网应激与软骨细胞自噬、凋亡在OA发病中的作用尚未见报道。本课题组预初研究发现OA病人软骨中的内质网应激相关蛋白表达升高。本课题拟利用体外细胞试验和OA大鼠模型观察内质网应激对软骨细胞自噬和凋亡的影响，观察抑制细胞自噬后软骨细胞凋亡的变化，明确内质网应激介导的软骨细胞自噬和凋亡在OA发病中的作用。通过检测OA病人关节软骨和血清中的内质网应激相关蛋白和细胞自噬标志物的表达，进一步明确内质网应激、自噬和凋亡在OA发病中的重要作用，为OA的防治提供新的思路。

骨关节炎是一种累及关节软骨及软骨下骨一种炎症性性疾病。 目前临床上常用的治疗骨关节炎的药物主要是缓解疼痛这一主要临床症状，且有很多副作用。因此，寻找一种更新更安全有效的治疗骨关节炎的药物成为临床迫切需要。 姜黄素是从草本植物姜黄的根茎中提取出来的酚类色素，是姜黄的主要成分。很多研究表明姜黄素具有抗炎、抗氧化应激、抗分解代谢的作用，从而能够缓解骨关节炎的病理进展和症状。在本课题中，我们探讨了姜黄素对IL-1β刺激的原代关节软骨细胞的保护作用的机制。我们结果发现，IL-1β对软骨细胞增殖的抑制呈剂量和时间依赖性。姜黄素能够减轻IL-1β对细胞增殖的抑制。IL-1β能够诱导软骨细胞凋亡，激活caspase-3。姜黄素能够促进磷酸化Erk1/2和自噬标志物 LC3-Ⅱ、Beclin-1的表达。当用Erk1/2抑制剂U0126处理软骨细胞后，自噬标志物的表达下降。我们的研究结果提示，姜黄素通过Erk1/2通路诱导的自噬来抑制 IL-1β诱导的凋亡。本课题的研究结果为开发新的治疗骨关节炎的靶点提供了新的思路。