Activation of NRF2 by celastrol increases antioxidant functions and prevents the progression of osteoarthritis in mice

Abstract

Excessive oxidative stress impairs cartilage matrix metabolism balance, significantly contributing to osteoarthritis (OA) development. Celastrol (CSL), a drug derived from Tripterygium wilfordii, has recognized applications in the treatment of cancer and immune system disorders, yet its antioxidative stress mechanisms in OA remain underexplored. This study aimed to substantiate CSL's chondroprotective effects and unravel its underlying mechanisms. We investigated CSL's impact on chondrocytes under both normal and inflammatory conditions. In vitro, CSL mitigated interleukin (IL)-1β-induced activation of proteinases and promoted cartilage extracellular matrix (ECM) synthesis. In vivo, intra-articular injection of CSL ameliorated cartilage degeneration and mitigated subchondral bone lesions in OA mice. Mechanistically, it was found that inhibiting nuclear factor erythroid 2-related factor 2 (NRF2) abrogated CSL-mediated antioxidative functions and exacerbated the progression of OA. This study is the first to elucidate the role of CSL in the treatment of OA through the activation of NRF2, offering a novel therapeutic avenue for arthritis therapy.