Melittin alleviates osteoarthritis via mitophagy mediated by the AMPK/PINK1/Parkin Axis

Osteoarthritis (OA) is a common degenerative joint disease, mainly characterized by cartilage extracellular matrix (ECM) degradation, inflammatory response and chondrocyte apoptosis, with mitochondrial dysfunction as its key pathogenic factor. Melittin (Mel), the main active component of bee venom, has been confirmed to possess anti-inflammatory, antioxidant and anti-apoptotic effects, but its therapeutic effect and specific mechanism on OA have not been fully elucidated. This study explored the therapeutic effect and mechanism of Mel on OA through in vitro and in vivo experiments. In vitro experiments showed that Mel could dose-dependently reverse IL-1β-induced OA-like changes in rat chondrocytes: it not only upregulated ECM anabolic markers such as type II collagen (COL2) and aggrecan (ACAN), downregulated ECM catabolic markers such as matrix metalloproteinase-13 (MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS5), but also inhibited inflammatory markers such as IL-1β, IL-18, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), while restoring PINK1/Parkin-mediated mitophagy. Mechanistically, Mel exerted a protective effect against the pathological progression of OA induced by destabilization of the medial meniscus (DMM). In conclusion, Mel is expected to be a potential candidate for OA treatment.