Muscone ameliorates osteoarthritis progression by inhibiting M1 macrophages polarization via Nrf2/NF-κB axis and protecting chondrocytes.

Osteoarthritis (OA) is a common and chronic joint condition marked by the deterioration of cartilage, osteophyte formation, and synovial inflammation (synovitis), severely impairing physical function and quality of life. The synovitis is crucial for initiation and exacerbation of OA. Muscone, the main bioactive compound found in musk, exhibits anti-inflammatory, antioxidant, and neuroprotective effects. Nevertheless, it is still uncertain whether Muscone alleviates the progression of OA by suppressing inflammation. Our research investigated how Muscone affected M1 macrophage polarization and joint inflammation in vitro, as well as its effects on OA progression in vivo. Our findings showed that Muscone significantly inhibited pro-inflammatory cytokine secretion and M1 polarization in LPS-induced RAW264.7 macrophages. Moreover, Muscone suppressed synovitis by impeding pro-inflammatory and M1-related factors in synovium of OA mice. Mechanistic investigations revealed Muscone directly bound Nrf2 and promoted its nuclear translation in LPS-induced RAW264.7 cells, while also simultaneously suppressing the phosphorylation of P65 and IκBα within the NF-κB signaling pathway. Moreover, the pharmacological blockade of Nrf2 partially mitigated the influence of Muscone on LPS-triggered M1 macrophage polarization and the NF-κB pathway. Furthermore, Muscone slowed down the degeneration of articular cartilage in OA mice by promoting chondrocyte anabolism and simultaneously inhibiting inflammation, catabolic processes, and apoptosis of chondrocytes. Overall, our findings indicate that Muscone mitigates the advancement of OA through the inhibition of M1 macrophage polarization and the protection of chondrocytes, thus highlighting its potential as a therapeutic candidate for OA treatment.