Bardoxolone-Methyl 可预防体外氧化应激介导的细胞凋亡和细胞外基质降解，并减轻体内骨关节炎。

PURPOSE: Oxidative stress-induced chondrocyte apoptosis and extracellular matrix (ECM) degradation plays an important role in the progression of osteoarthritis (OA). Bardoxolone methyl (BM), a semisynthetic triterpenoid, exerts strong effect against oxidative stress. The purpose of the present study was to determine the effectiveness of bardoxolone-methyl (BM) in preventing oxidative stress-induced chondrocyte apoptosis and extracellular ECM degradation in vitro and the role of alleviating OA progression in vivo. METHODS: Oxidative damage was induced by 25 mM tert-butyl hydroperoxide (TBHP) for 24 h in rat chondrocytes. 0.025 and 0.05 µM bardoxolone-methyl (BM) were used in vitro treatment. Ex-vivo cartilage explant model was established to evaluate the effect of BM on oxidative stress-induced ECM degradation. The mouse OA model was induced by surgical destabilization of the medial meniscus. RESULTS: In vitro, 0.025 and 0.05 µM BM reduced TBHP-induced excessive ROS generation, improved cell viability, increased malondialdehyde level and decreased superoxide dismutase level. 0.025 and 0.05 µM BM prevented TBHP-induced mitochondrial damage and apoptosis in chondrocytes BM activated heme oxygenase-1 (HO-1)/NADPH quinone oxidoreductase 1 (NOQ1) signaling pathway through targeting nuclear factor erythroid derived-2-related factor 2 (Nrf2). Additionally, BM treatment enhanced the expression levels of aggrecan and collagen II and inhibited the expression levels of matrix metalloproteinase 9 (MMP 9), MMP 13, Bax and cleaved-caspase-3. BM increased proteoglycan staining area and IOD value in ex vivo cultured experiment cartilage explants and improved the OARSI score, stands, max contact mean intensity, print area and duty cycle in mouse OA model. CONCLUSION: BM prevented oxidative stress-induced chondrocyte apoptosis and ECM degradation in vitro and alleviated OA in vivo, suggesting that BM serves as an effective drug for treatment with OA.

目的：氧化应激诱导的软骨细胞凋亡和细胞外基质（ECM）降解在骨关节炎（OA）的进展中起着重要作用。Bardoxolone 甲基（BM），一种半合成三萜，对氧化应激有很强的作用。本研究的目的是确定 bardoxolone 甲基（BM）在预防体外氧化应激诱导的软骨细胞凋亡和细胞外 ECM 降解中的有效性，并确定其在体内缓解 OA 进展中的作用。

方法：用 25mM 叔丁基过氧化氢（TBHP）处理大鼠软骨细胞 24 小时诱导氧化损伤。在体外治疗中使用 0.025 和 0.05μM bardoxolone 甲基（BM）。建立离体软骨外植体模型以评估 BM 对氧化应激诱导的 ECM 降解的影响。通过内侧半月板手术不稳定诱导小鼠 OA 模型。

结果：在体外，0.025 和 0.05μM BM 减少 TBHP 诱导的过量 ROS 生成，提高细胞活力，增加丙二醛水平，降低超氧化物歧化酶水平。0.025 和 0.05μM BM 防止 TBHP 诱导的软骨细胞中线粒体损伤和凋亡。BM 通过靶向核因子红细胞衍生 2 相关因子 2（Nrf2）激活血红素加氧酶-1（HO-1）/NADPH 醌氧化还原酶 1（NOQ1）信号通路。此外，BM 治疗增强了聚集蛋白聚糖和胶原 II 的表达水平，并抑制了基质金属蛋白酶 9（MMP 9）、MMP 13、Bax 和 cleaved-caspase-3 的表达水平。BM 增加了体外培养实验软骨外植体中糖胺聚糖的染色面积和 IOD 值，并改善了小鼠 OA 模型中的 OARSI 评分、站立、最大接触平均强度、打印面积和占空比。

结论：BM 可预防体外氧化应激诱导的软骨细胞凋亡和 ECM 降解，并减轻体内 OA，表明 BM 可作为治疗 OA 的有效药物。