Therapeutic Effects of WIN55,212-2 on Temporomandibular Joint Osteoarthritis in a Rat Model and Primary Temporomandibular Joint Condylar Chondrocytes.

INTRODUCTION/OBJECTIVE: This study investigates the therapeutic potential of the synthetic cannabinoid WIN55,212-2 (WIN55) in temporomandibular joint osteoarthritis (TMJOA), focusing on its capacity to attenuate cartilage degradation and modulate inflammatory pathways, thereby providing preclinical evidence to support future clinical translation. METHODS: A monosodium iodoacetate (MIA)-induced TMJOA model was established in rats, followed by WIN55 treatment. Cartilage integrity and subchondral bone structure were evaluated using histological and imaging techniques. Primary condylar chondrocytes were treated with IL-1β and WIN55 to elucidate the underlying inflammatory and molecular mechanisms through transcriptomic and protein-level analyses. RESULTS: WIN55 significantly alleviated cartilage degradation in TMJOA, as evidenced by improved histological scores, preserved proteoglycan content, and maintained subchondral bone architecture. in vitro, WIN55 suppressed IL-1β-induced pro-inflammatory cytokines (e.g., Il-6, Tnf-α) and chemokines (e.g., Ccl2, Ccl5, Cxcl1). Transcriptomic analysis revealed that WIN55 reversed key inflammatory pathways, including TNF and IL-17 signaling, and downregulated IL-1β-induced colony-stimulating factors (Csf1, Csf2, Csf3). Additionally, WIN55 modulated the expression profiles of lncRNAs and circRNAs. DISCUSSION: These findings provide the first comprehensive evidence that WIN55 exerts multi-target anti-inflammatory and chondroprotective effects in the TMJ context. By suppressing chemokine networks, CSF family members, and matrix-degrading enzymes while preserving extracellular matrix homeostasis, WIN55 addresses both inflammatory and degradative processes central to TMJOA pathogenesis. Modulation of non-coding RNAs suggests additional regulatory layers that may be exploited in future therapeutic strategies. CONCLUSION: WIN55 demonstrates significant therapeutic potential for TMJOA by mitigating cartilage degradation and modulating inflammatory responses. These findings highlight the promise of cannabinoid-based therapies for TMJOA and establish a foundation for subsequent clinical investigation.