Ergosterol limits osteoarthritis development and progression through activation of Nrf2 signaling

Osteoarthritis (OA) is a common joint disorder characterized by progressive articular cartilage degeneration and destruction and results in gradual disability among middle-aged and elderly patients. Our previous study demonstrated that depletion of nuclear factor erythroid 2-related factor 2 (Nrf2) exacerbated cartilage erosion in an OA model and that activation of the Nrf2 pathway could counter this process. As a downstream target of Nrf2, heme oxygenase (HO) degrades heme to free iron, biliverdin and carbon monoxide (CO), which protects against oxidative stress. Ergosterol (ER), which is extracted from fungi, is a newly discovered Nrf2 activator and displayed efficacy against myocardial injury. The present study aimed to investigate the potential protective effects of ER against cartilage damage during OA. Primary mouse chondrocytes were treated with ER for in vitro assays. Furthermore, mice that underwent destabilization of the medial meniscus surgery were orally administered with ER. Western blotting suggested that ER increased protein expression of Nrf2 and HO-1 in primary chondrocytes and articular cartilage from knee joints. Cartilage damage in knee joints was significantly reduced by ER treatment. Western blotting and PCR analysis confirmed that ER could also suppress the expression of MMP-9 and MMP-13 in vivo and in vitro. The present findings suggested that ER effectively alleviated cartilage degradation and that activation of the Nrf2-heme oxygenase 1 pathway may play a role in ER-mediated cartilage protection against OA.