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

Abstract

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.

Keywords:

• osteoarthritis
• chondrocyte apoptosis
• extracellular matrix degradation
• oxidative stress
• bardoxolone-methyl

Abbreviations

OA, osteoarthritis; ROS, reactive oxygen species; ECM, extracellular matrix; BM: Bardoxolone-methyl; Nrf2, nuclear factor erythroid derived-2-related factor 2; Keap1, Kelch-like ECH-associated protein 1; NQO1, NADPH quinone oxidoreductase 1; HO-1, heme oxygenase-1; MMP, matrix metalloproteinase; MDA, Malondialdehyde; SOD, superoxide dismutase.

Data Sharing Statement

The datasets used during the present study are available from the corresponding author upon reasonable request.

Author Contributions

All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

Dr Lu Cao reports grants from Shanghai Municipal Health Commission, during the conduct of the study. The author reports no conflicts of interest in this work.

Additional information

Funding

The work was supported by grants from National Natural Science Foundation of China (81672142), “Rising Stars of Medical Talent” Youth Development Program (Shangahai Municipal Health Commission 2019-72), and grants from Shanghai Science and Technology Commission (21ZR1412100).