Chen Jian, Xuan Jun, Gu Yun-Tao, Shi Ke-Si, Xie Jun-Jun, Chen Jiao-Xiang, Zheng Zeng-Ming, Chen Yu, Chen Xi-Bang, Wu Yao-Sen, Zhang Xiao-Lei, Wang Xiang-Yang
Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
Jinhua Municipal Central Hospital, Jinhua Hospital of Zhejiang University, People's Republic of China.
Biomed Pharmacother. 2017 Jul;91:208-219. doi: 10.1016/j.biopha.2017.04.093. Epub 2017 Apr 28.
Celastrol has been reported to exert therapeutic potential on pro-inflammatory diseases including asthma, Crohn's disease, arthritis and neurodegenerative disorders via inhibiting NF-κB pathway. While the effect of celastrol on intervertebral disc degeneration (IDD), which is also a pro-inflammatory disease, remains unknown. In this study, we evaluated the effect of celastrol on IDD in IL-1β treated human nucleus pulposus cells in vitro as well as in puncture induced rat IDD model in vivo. Our results showed that celastrol reduced the expression of catabolic genes (MMP-3, 9, 13, ADAMTS-4, 5), oxidative stress factors (COX-2, iNOS) and pro-inflammatory factors (IL-6, TNF-a) induced by IL-1β in nucleus pulposus cells, also phosphorylation of IκBα and p65 were attenuated by celastrol, indicating NF-κB pathway was inhibited by celastrol in nucleus pulposus cells. In vivo study showed that celastrol treated rats had stronger T2-weighted signal than vehicle-treated rats at 2 weeks and 6 weeks' time point, suggesting celastrol could attenuate intervertebral disc degeneration in vivo. Together, our study demonstrates that celastrol could reduce IL-1β induced matrix catabolism, oxidative stress and inflammation in human nucleus pulposus cells and attenuates rat intervertebral disc degeneration in vivo, which shows its potential to be a therapeutic drug for IDD.
据报道，雷公藤红素通过抑制核因子κB（NF-κB）信号通路，对包括哮喘、克罗恩病、关节炎和神经退行性疾病在内的促炎性疾病具有治疗潜力。然而，雷公藤红素对同样属于促炎性疾病的椎间盘退变（IDD）的影响尚不清楚。在本研究中，我们评估了雷公藤红素在体外对白细胞介素-1β（IL-1β）处理的人髓核细胞以及在体内对穿刺诱导的大鼠IDD模型中IDD的影响。我们的结果表明，雷公藤红素降低了髓核细胞中由IL-1β诱导的分解代谢基因（基质金属蛋白酶-3、9、13、含血小板反应蛋白基序的解聚蛋白样金属蛋白酶-4、5）、氧化应激因子（环氧化酶-2、诱导型一氧化氮合酶）和促炎因子（IL-6、肿瘤坏死因子-α）的表达，雷公藤红素还减弱了IκBα和p65的磷酸化，表明雷公藤红素在髓核细胞中抑制了NF-κB信号通路。体内研究表明，在2周和6周时间点，雷公藤红素处理的大鼠比载体处理的大鼠具有更强的T2加权信号，提示雷公藤红素可在体内减轻椎间盘退变。总之，我们的研究表明，雷公藤红素可减少IL-1β诱导的人髓核细胞中的基质分解代谢、氧化应激和炎症，并在体内减轻大鼠椎间盘退变，这表明其有潜力成为一种治疗IDD的药物。
