Sinomenine regulates macrophage reprogramming via the PI3K-AKT-NF-κB pathway to ameliorate osteoarthritis

Osteoarthritis (OA) is a chronic joint disease characterized by structural cartilage damage and inflammatory changes in the synovium. The macrophage response, especially the activation of M1-type macrophages, represents a key mechanism underlying OA pathogenesis. Rheumatic and immune-related disorders may benefit from sinomenine treatment, a natural substance with immunomodulatory and anti-inflammatory properties. Here, human synovial tissues were collected from OA patients and healthy controls (n = 6 per group), and an ACLT-induced OA rat model was established (n = 6 per group). In vitro experiments were performed in RAW264.7 macrophages and SW1353 chondrocytes with three independent biological replicates for each experiment. These experiments were performed to investigate the regulatory effects of sinomenine on M1/M2 macrophage polarization and inflammatory cytokine expression. An ACLT-induced OA rat model was used to determine the effects of sinomenine on cartilage lesions, synovial inflammatory responses, and matrix metabolic alterations. Primary outcomes were M1/M2 macrophage polarization status and synovial inflammatory response. Secondary outcomes included cartilage matrix metabolic changes and chondrocyte function. Sinomenine dramatically increased CD206 levels in macrophages and suppressed LPS-induced iNOS expression (P < 0.001). Additional research revealed that sinomenine altered macrophage polarization by increasing IL-10 levels in M2 macrophages and decreasing TNF-α levels in M1 macrophages (P < 0.001). Sinomenine significantly decreased synovial inflammation and cartilage damage in OA rats and restored cartilage matrix homeostasis. Immunohistochemistry revealed that sinomenine reduced MMP13 expression and increased COL2 synthesis (P < 0.001). This study confirms that sinomenine can alleviate synovial inflammation and promote cartilage repair in OA by modulating macrophage polarization, suggesting a novel strategy for OA treatment.