Bardoxolone-Methyl Prevents Oxidative Stress-Mediated Apoptosis and Extracellular Matrix Degradation in vitro and Alleviates Osteoarthritis in vivo

Abstract

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.

The role of oxidative stress in the development of knee osteoarthritis: A comprehensive research review

“…Karim et al found that iron overload in chondrocytes can induce oxidative stress, cell cycle arrest and apoptosis (Karim et al, 2022). Pang et al found that Bardoxolonemethyl can inhibit chondrocyte apoptosis and ECM degradation induced by oxidative stress in vitro, and reduce OA in vivo (Pang et al, 2021).…”

Patchouli Alcohol Inhibits D-Gal Induced Oxidative Stress and Ameliorates the Quality of Aging Cartilage via Activating the Nrf2/HO-1 Pathway in Mice

“…Senescent chondrocytes exhibit telomere shortening with age and the nonreplicative senescence of chondrocytes mainly induced by external or endogenous stress, such as reactive oxygen species (ROS) [ 6 ]. Previous studies have confirmed that extravagant levels of ROS could, in turn, aggravate senescence and set off pathological modifications of cellular proteins and lipids, thereby restraining chondrocyte activity and destroying ECM homeostasis, finally giving rise to damage of articular cartilage [ 7 , 8 ]. Thus, inhibition of chondrocyte oxidative stress is proposed as an effective remedy strategy for senile cartilage quality loss.…”

Bardoxolone Methyl Ameliorates Compression-Induced Oxidative Stress Damage of Nucleus Pulposus Cells and Intervertebral Disc Degeneration Ex Vivo

“…Oxidative stress can accelerate the process of IDD in many ways, including through apoptosis, ECM degeneration, senescence, and autophagy (Feng et al, 2017). Many reports have shown that BARD has a strong antioxidative effect (Khurana et al, 2020;Pang et al, 2021;Snijders et al, 2021). However, whether BARD can alleviate IVD degeneration caused by compression has not been studied.…”