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Corosolic Acid Protects Rat Chondrocytes Against IL-1β-Induced ECM Degradation by Activating Autophagy via PI3K/AKT/mTOR Pathway and Ameliorates Rat Osteoarthritis
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2022-08-06 , DOI: 10.2147/dddt.s365279 Hui Han 1, 2, 3 , Ming Chen 2 , Zhenyu Li 2 , Siqi Zhou 2 , Yingbin Wu 3 , Jian Wei 1
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2022-08-06 , DOI: 10.2147/dddt.s365279 Hui Han 1, 2, 3 , Ming Chen 2 , Zhenyu Li 2 , Siqi Zhou 2 , Yingbin Wu 3 , Jian Wei 1
Affiliation
Purpose: Osteoarthritis (OA) is an age-related degenerative disease associated with enhanced degradation of extracellular matrix (ECM) and decreased autophagy. Our study is aimed to explore how corosolic acid (CRA) affect cartilage ECM metabolism and the potential mechanism.
Methods: Rat chondrocytes were pretreated with different concentrations of CRA (0, 2.5, 5, and 10 μM), and were stimulated with IL-1β (10ng/mL) for 24 h, subsequently. RT-qPCR, Western blot, and immunofluorescence were used to detect the expression of genes related to ECM metabolism and explore the potential molecular mechanism. The effect of CRA on articular cartilage was observed in the surgically induced OA rat model with the method of Safranin O/Fast green and immunohistochemical staining.
Results: Results showed that CRA reversed the IL-1β-induced degradation of aggrecan and type II collagen and the high expression of MMP13 and ADAMTS5. Mechanistically, CRA enhanced autophagy through inhibiting the classical PI3K/AKT/mTOR signaling pathway. Furthermore, inhibition of autophagy partly abolished the protective effects of CRA on ECM synthesis in IL-1β-treated chondrocytes. Correspondingly, the protective effect of CRA was also confirmed in a rat OA model.
Conclusion: Herein, we demonstrate that CRA can enhance autophagy by inhibiting PI3K/AKT/mTOR signaling pathway, prevent IL-1β-induced cartilage ECM degradation, and may be a potentially applicable candidate for the treatment of OA.
Keywords: osteoarthritis, corosolic acid, autophagy, extracellular matrix, PI3K/AKT/mTOR signaling
中文翻译：
科罗索酸通过 PI3K/AKT/mTOR 通路激活自噬保护大鼠软骨细胞免受 IL-1β 诱导的 ECM 降解并改善大鼠骨关节炎
目的：骨关节炎（OA）是一种与年龄相关的退行性疾病，与细胞外基质（ECM）降解增强和自噬减少有关。我们的研究旨在探索科罗索酸（CRA）如何影响软骨ECM代谢及其潜在机制。
方法：大鼠软骨细胞用不同浓度的CRA（0、2.5、5和10 μM）预处理，随后用IL-1β（10ng/mL）刺激24 h。采用RT-qPCR、Western blot和免疫荧光检测ECM代谢相关基因的表达，探索潜在的分子机制。用番红O/Fast green和免疫组化染色法在手术诱导的OA大鼠模型中观察CRA对关节软骨的影响。
结果：结果表明，CRA 逆转了 IL-1β 诱导的蛋白聚糖和 II 型胶原蛋白的降解以及 MMP13 和 ADAMTS5 的高表达。从机制上讲，CRA 通过抑制经典的 PI3K/AKT/mTOR 信号通路增强自噬。此外，自噬的抑制部分消除了 CRA 对 IL-1β 处理的软骨细胞中 ECM 合成的保护作用。相应地，CRA的保护作用也在大鼠OA模型中得到证实。
结论：在此，我们证明 CRA 可以通过抑制 PI3K/AKT/mTOR 信号通路增强自噬，防止 IL-1β 诱导的软骨 ECM 降解，可能是治疗 OA 的潜在适用候选者。
关键词：骨关节炎，科罗索酸，自噬，细胞外基质，PI3K/AKT/mTOR信号
更新日期：2022-08-06
Methods: Rat chondrocytes were pretreated with different concentrations of CRA (0, 2.5, 5, and 10 μM), and were stimulated with IL-1β (10ng/mL) for 24 h, subsequently. RT-qPCR, Western blot, and immunofluorescence were used to detect the expression of genes related to ECM metabolism and explore the potential molecular mechanism. The effect of CRA on articular cartilage was observed in the surgically induced OA rat model with the method of Safranin O/Fast green and immunohistochemical staining.
Results: Results showed that CRA reversed the IL-1β-induced degradation of aggrecan and type II collagen and the high expression of MMP13 and ADAMTS5. Mechanistically, CRA enhanced autophagy through inhibiting the classical PI3K/AKT/mTOR signaling pathway. Furthermore, inhibition of autophagy partly abolished the protective effects of CRA on ECM synthesis in IL-1β-treated chondrocytes. Correspondingly, the protective effect of CRA was also confirmed in a rat OA model.
Conclusion: Herein, we demonstrate that CRA can enhance autophagy by inhibiting PI3K/AKT/mTOR signaling pathway, prevent IL-1β-induced cartilage ECM degradation, and may be a potentially applicable candidate for the treatment of OA.
Keywords: osteoarthritis, corosolic acid, autophagy, extracellular matrix, PI3K/AKT/mTOR signaling
中文翻译：
科罗索酸通过 PI3K/AKT/mTOR 通路激活自噬保护大鼠软骨细胞免受 IL-1β 诱导的 ECM 降解并改善大鼠骨关节炎
目的：骨关节炎（OA）是一种与年龄相关的退行性疾病，与细胞外基质（ECM）降解增强和自噬减少有关。我们的研究旨在探索科罗索酸（CRA）如何影响软骨ECM代谢及其潜在机制。
方法：大鼠软骨细胞用不同浓度的CRA（0、2.5、5和10 μM）预处理，随后用IL-1β（10ng/mL）刺激24 h。采用RT-qPCR、Western blot和免疫荧光检测ECM代谢相关基因的表达，探索潜在的分子机制。用番红O/Fast green和免疫组化染色法在手术诱导的OA大鼠模型中观察CRA对关节软骨的影响。
结果：结果表明，CRA 逆转了 IL-1β 诱导的蛋白聚糖和 II 型胶原蛋白的降解以及 MMP13 和 ADAMTS5 的高表达。从机制上讲，CRA 通过抑制经典的 PI3K/AKT/mTOR 信号通路增强自噬。此外，自噬的抑制部分消除了 CRA 对 IL-1β 处理的软骨细胞中 ECM 合成的保护作用。相应地，CRA的保护作用也在大鼠OA模型中得到证实。
结论：在此，我们证明 CRA 可以通过抑制 PI3K/AKT/mTOR 信号通路增强自噬，防止 IL-1β 诱导的软骨 ECM 降解，可能是治疗 OA 的潜在适用候选者。
关键词：骨关节炎，科罗索酸，自噬，细胞外基质，PI3K/AKT/mTOR信号
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