Cyasterone Improves Mitochondrial Function and Protects against Knee Osteoarthritis by Activating PPARγ

Introduction: Studies have demonstrated that mitochondrial dysfunction plays an important role in the development of knee osteoarthritis. Our previous study reported that cyasterone accelerates fracture healing by promoting the migration and osteogenesis of mesenchymal stem cells (MSCs). However, the effect of cyasterone on osteoarthritis (OA) has not been investigated. Therefore, this study aimed to investigate the effects of cyasterone on mitochondrial function in chondrocytes of mice and its potential therapeutic impact on knee osteoarthritis (OA) in mice.

Methods: Primary chondrocytes were isolated from C57BL/6 mice, and the optimal cyasterone concentration was determined via CCK-8 assay. An osteoarthritis chondrocyte model was established using lipopolysaccharide (LPS) induction. Chondrocytes were assigned to control, LPS, and cyasterone treatment groups. ATP production, NAD+/NADH ratio, oxidative stress levels, and mitochondrial membrane potential were measured in each group. Adult C57BL/6 mice were allocated into three groups (n=8 per group): control, model, and cyasterone treatment. After 4 weeks of cyasterone intervention, histopathological changes in knee joints and expression of extracellular matrix-related proteins in cartilage tissue were assessed.

Results: Compared to the LPS group, cyasterone treatment significantly increased ATP production, elevated the NAD+/NADH ratio, and reduced oxidative stress levels in LPS- induced chondrocytes. Mechanically, we found that the expression of Peroxisome proliferator- activated receptor γ (PPARγ) was significantly increased by cyasterone. In the OA group treated with cyasterone, the mice exhibited marked improvement in cartilage histopathological scores compared to the model group, with enhanced expression of aggrecan and PPARγ proteins and decreased expression levels of MMP13 and phosphorylated- p65.

Discussion: Consistent with previous findings, our results showed that cyasterone significantly increased PPARγ expression in primary chondrocytes, thereby maintaining chondrocyte function and preventing the progression of OA.

Conclusion: In summary, the results indicated that cyasterone could restore mitochondrial function in LPS-induced mouse chondrocytes by upregulating PPARγ expression. in vivo, cyasterone was found to reduce extracellular matrix degradation and inhibit the progression of osteoarthritis (OA). These findings suggest that cyasterone could be a potential natural compound for the effective treatment of OA.