School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK.
Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China.
Cell Biol Int. 2021 May;45(5):976-988. doi: 10.1002/cbin.11541. Epub 2021 Jan 25.
Articular cartilage damage and chondrocyte apoptosis are common features of rheumatoid arthritis and osteoarthritis. Recently, curcumin has been reported to exhibit protective effects on degeneration in articular cartilage diseases. However, the effects and mechanisms of curcumin on articular chondrocyte injury remain to be elucidated. The aim of the present study is to investigate the chondroprotective mechanisms of curcumin on interleukin-1β (IL-1β)-induced chondrocyte apoptosis in vitro. The results revealed that IL-1β decreased cell viability and induced apoptosis in primary articular chondrocytes. Curcumin pretreatment reduced IL-1β-induced articular chondrocyte apoptosis. In addition, treatment with curcumin increased autophagy in articular chondrocytes and protected against IL-1β-induced apoptosis. The curcumin-mediated protection against IL-1β induced apoptosis was abolished when cells were treated with the autophagy inhibitor 3-methyladenine or transfected with Beclin-1 small interfering RNA. Furthermore, IL-1β stimulation significantly increased the phosphorylation levels of nuclear factor (NF)-κB p65 and glycogen synthase kinase-3β, and decreased the phosphorylation levels of β-catenin in articular chondrocytes, and these alterations to the phosphorylation levels were partly reversed by treatment with curcumin. Dual-luciferase and electrophoretic mobility shift assays demonstrated that IL-1β increased NF-κB p65 promoter activity in chondrocytes, and this was also reversed by curcumin. Pretreatment with the NF-κB inhibitor pyrrolidine dithiocarbamate enhanced the protective effects of curcumin on chondrocyte apoptosis, but Wnt/β-catenin inhibitor, XAV-939, did not exhibit this effect. Molecular docking and dynamic simulation studies results showed that curcumin could bound to RelA (p65) protein. These results indicate that curcumin may suppress IL-1β-induced chondrocyte apoptosis through activating autophagy and restraining NF-κB signaling pathway.
关节软骨损伤和软骨细胞凋亡是类风湿关节炎和骨关节炎的共同特征。最近，姜黄素已被报道对关节软骨疾病的退行性变具有保护作用。然而，姜黄素对关节软骨细胞损伤的作用及其机制仍有待阐明。本研究旨在探讨姜黄素对白细胞介素-1β（IL-1β）诱导的体外软骨细胞凋亡的保护机制。结果表明，IL-1β降低了原代关节软骨细胞的活力并诱导其凋亡。姜黄素预处理可减少 IL-1β诱导的关节软骨细胞凋亡。此外，姜黄素处理可增加关节软骨细胞中的自噬，并防止 IL-1β诱导的凋亡。在用自噬抑制剂 3-甲基腺嘌呤或 Beclin-1 小干扰 RNA 转染的细胞中，姜黄素介导的对 IL-1β诱导的凋亡的保护作用被消除。此外，IL-1β刺激显著增加了核因子（NF）-κB p65 和糖原合酶激酶-3β的磷酸化水平，降低了关节软骨细胞中β-连环蛋白的磷酸化水平，而姜黄素处理部分逆转了这些磷酸化水平的变化。双荧光素酶和电泳迁移率变动分析表明，IL-1β增加了软骨细胞中 NF-κB p65 启动子的活性，而姜黄素也逆转了这一作用。NF-κB 抑制剂吡咯烷二硫代氨基甲酸盐预处理增强了姜黄素对软骨细胞凋亡的保护作用，而 Wnt/β-连环蛋白抑制剂 XAV-939 则没有这种作用。分子对接和动态模拟研究结果表明，姜黄素可以与 RelA（p65）蛋白结合。这些结果表明，姜黄素可能通过激活自噬和抑制 NF-κB 信号通路来抑制 IL-1β诱导的软骨细胞凋亡。
