CDDO-Im ameliorates osteoarthritis and inhibits chondrocyte apoptosis in mice via enhancing Nrf2-dependent autophagy
CDDO-Im ameliorates osteoarthritis and inhibits chondrocyte apoptosis in mice via enhancing Nrf2-dependent autophagy
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DOI：
10.1038/s41401-021-00782-6
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发表时间：
2021-11-09
影响因子：
8.2
通讯作者：
Jiang, Qing
中科院分区：
文献类型：
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作者：
Dong, Jian;Zhang, Kai-Jia;Jiang, Qing
骨关节炎（OA）是最常见的慢性退行性关节疾病，治疗方法很少。骨性关节炎的发病机制以持续炎症、氧化应激和软骨细胞凋亡为特征，最终导致软骨退化和关节功能障碍。在本研究中，我们发现了一种合成的三萜CDDO-Im（1-[2-氰-3,12-二氧齐烷-1,9(11)-二烯-28-油基]咪唑）作为Nrf2（核因子红细胞2相关因子2）的激活剂，具有很强的抗oa作用。我们发现CDDO-Im （20 nM）可显著缓解tnf α诱导的人软骨细胞凋亡和细胞外基质降解。在DMM（内侧半月板不稳定）引起的小鼠OA模型中，给予CDDO-Im （2.5 mg/kg, ip，每隔一天，持续8周）有效降低膝关节软骨侵蚀和血清炎症因子IL-1 β和IL-6水平。我们发现CDDO-Im （20 nM）显著增强了软骨细胞的自噬活性，而氯喹（CQ, 50 μ M）或3-甲基腺嘌呤（3-MA, 5 mM）对自噬的抑制作用则削弱了CDDO-Im对tnf α处理的软骨细胞的抗凋亡和软骨保护作用。此外，我们证实了CDDO-Im （1-20 nM）在tnf - α处理的软骨细胞中剂量依赖性激活Nrf2通路，当Nrf2信号被Nrf2抑制剂ML385 （20 μ M）或sirna介导的Nrf2敲低阻断时，其软骨保护和自噬增强作用显著减弱。总之，我们的研究结果表明，由于其Nrf2激活和自噬增强特性，cdo - im具有突出的软骨保护和抗OA活性，这可能为OA的临床预防和治疗策略提供新的见解。
Osteoarthritis (OA) is the most prevalent chronic degenerative joint disease with few treatment options. The pathogenesis of OA is characterized by sustained inflammation, oxidative stress and chondrocyte apoptosis that eventually lead to cartilage degradation and joint dysfunction. In the present study, we identified a synthetic triterpenoid CDDO-Im(1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole) as an activator of Nrf2 (nuclear factor erythroid 2-related factor 2) that displayed strong anti-OA effects. We showed that CDDO-Im (20 nM) significantly alleviated TNF-alpha-induced apoptosis of primary human chondrocytes and extracellular matrix degradation. In a mouse OA model incurred by DMM (destabilization of medial meniscus), administration of CDDO-Im (2.5 mg/kg, ip, every other day for 8 weeks) effectively reduced knee joint cartilage erosion and serum levels of inflammatory cytokines IL-1 beta and IL-6. We revealed that CDDO-Im (20 nM) significantly enhanced autophagy activities in chondrocytes, whereas the autophagy inhibition by chloroquine (CQ, 50 mu M) or 3-methyladenine (3-MA, 5 mM) abrogated the anti-apoptosis and chondroprotective effects of CDDO-Im in TNF-alpha-treated chondrocytes. Moreover, we confirmed that CDDO-Im (1-20 nM) dose-dependently activated Nrf2 pathway in TNF-alpha-treated chondrocytes, and its chondroprotective and autophagy-enhancing effects were significantly diminished when Nrf2 signaling was blocked by Nrf2 inhibitor ML385 (20 mu M) or siRNA-mediated Nrf2 knockdown. Together, our results demonstrate that CDDO-Im exhibits prominent chondroprotective and anti-OA activities owing to its Nrf2 activation and autophagy-enhancing properties, which might provide new insights into the strategies of OA clinical prevention and treatment.