阿托伐他汀钙经STAT1-caspase-3信号轴抑制膝骨关节炎大鼠关节软骨退变的研究

Inhibition of articular cartilage degeneration by atorvastatin calcium via STAT1-caspase-3 signaling axis in rats with knee osteoarthritis

目的:探讨阿托伐他汀钙在膝骨关节炎(KOA)大鼠体内通过调节信号转导和转录激活因子1(STAT1)、半胱氨酸蛋白酶-3(caspase-3)的表达,从而对关节软骨退变的影响。方法:将SD大鼠随机分为正常对照组、模型组、阿托伐他汀钙治疗组,采用Hulth法建立KOA大鼠模型,实验8周后采用酶联免疫吸附测定(ELISA)法检测大鼠血清中TNF-α及IL-1β的表达水平,膝关节X线影像学检查,关节软骨HE染色行病理学观察,检测软骨组织内p-STAT1和cleaved caspase-3蛋白表达水平。结果:模型组大鼠血清中TNF-α及IL-1β含量明显高于正常组(P<0.01),而阿托伐他汀钙治疗组低于模型组(P<0.01)。阿托伐他汀钙治疗组X线表现与模型组相比,膝关节关节间隙、关节软骨破坏和骨赘形成等均有改善。阿托伐他汀钙能明显减轻膝关节病理变化,与模型组相比,阿托伐他汀钙治疗组关节软骨Mankin's评分显著降低(P<0.01)。模型组大鼠关节软骨p-STAT1和cleaved caspase-3蛋白表达水平明显高于正常组(P<0.01),而阿托伐他汀钙治疗组低于模型组(P<0.01),且相关分析表明,pSTAT1和cleaved caspase-3之间呈直线正相关(r=0.986,P<0.01)。结论:阿托伐他汀钙经STAT1-caspase-3信号轴抑制膝关节炎症反应,从而改善KOA关节软骨的退变。

AIM：To investigate the effect of atorvastatin calcium on the expression of STAT1,caspase-3 and on degeneration of articular cartilage in the knee osteoarthritis（KOA） rats.METHODS：SD rats were randomly divided into normal control group,model group and atorvastatin calcium treatment group.KOA rat model was established by Hulth method.After 8 weeks of experiment,the expression of TNF-α and IL-1β in serum of rats were detected by ELASA,X-ray examination was used to detect knee joint,articular cartilage HE staining were used for pathological observation,cartilage tissue p-STAT1 and cleaved caspase-3 protein expression levels were observed by immunohistochemistry and western blot.RESULTS：The levels of serum TNF-α and IL-1β in model group were significantly higher than those in normal group（P〈0.01）,while those in atorvastatin calcium group were lower than those in model group（P〈0.01）.Compared with the model group,the X-ray findings of atorvastatin calcium treatment group showed improvement of knee joint space,articular cartilage destruction and osteophyte formation.Atorvastatin calcium could significantly reduce the pathological changes of knee joint.Compared with model group,Mankin ＇s score of articular cartilage in atorvastatin calcium treatment group decreased significantly（P〈0.01）.The expression of p-STAT1 and cleaved caspase-3 protein in articular cartilage of model group was significantly higher than that of normal group（P〈0.01）,while that of atorvastatin calcium group was lower than that of model group（P〈0.01）,and the correlation analysis showed that there was a linear positive correlation between p-STAT1 and cleaved caspase-3（r =0.986,P〈0.01）.CONCLUSION：Atorvastatin inhibits the inflammation of the knee joint via STAT1-caspase-3 signal axis,thereby improving the degeneration of KOA articular cartilage.