Melatonin Attenuates Synovial Hyperplasia, Inflammation, and Fibrosis and Postpones Osteoarthritis Progression

Osteoarthritis (OA) is a prevalent disease of the whole joint, in which synovial hyperplasia, inflammation, and fibrosis are important pathological manifestations. Melatonin (MT) possesses diverse biological activities and has shown promise in mitigating cartilage degradation in OA. However, further research is required to clarify MT's effects and mechanisms on OA synovium. Fibroblast-like synoviocytes (FLSs) were isolated and identified by immunofluorescence. Cell counting kit-8, EdU, flow cytometry, transwell, and wound healing assays were employed to assess the proliferation, DNA replication, cell cycle, apoptosis, and migration of FLSs. TGF-β1 was used to induce inflammation and fibrosis in FLSs. Protein and mRNA expression levels were evaluated using Western blot, enzyme-linked immunosorbent assay, immunofluorescence, and real-time quantitative PCR. Additionally, an OA rabbit model was established, and the pathological changes of synovium, synovial fluid, cartilage, and subchondral bone were investigated to assess the in vivo effects of MT on OA. The proliferation, DNA replication, and expression of proliferating cell nuclear antigen (PCNA) and c-Myc of FLSs were inhibited by MT intervention. MT arrested the cell cycle by inhibiting the expression of cyclin D1 and cyclin E1, induced apoptosis via down-regulating B-cell lymphoma-2 (Bcl-2) and up-regulating Bcl-2 associated X (Bax), and suppressed the migration by impairing vimentin expression in FLSs. Mechanistically, MT exerted these effects by regulating the Hippo/YAP and PI3K/AKT pathways. Moreover, MT ameliorated synovial hyperplasia, inflammation, fibrosis, and pathological changes in synovial fluid, as well as the destruction of cartilage and bone in the OA rabbit model. Our findings indicate that MT alleviates synovial pathological changes and delays OA progression, which is related to its ability to suppress aberrant FLS functions.