Necrostatin-1 alleviates temporomandibular joint osteoarthritis and inhibits chondrocyte senescence and necroptosis possibly via p53/ MAPK downregulation

Temporomandibular joint osteoarthritis (TMJ-OA) is a prevalent oral and maxillofacial disorder characterized by a complex etiology and pathogenesis. Targeting and eliminating senescent chondrocytes is emerging as a promising therapeutic strategy for TMJ-OA. Necrostatin-1 (NEC1), a receptor-interacting protein kinase 1 (RIPK1)-targeted necroptosis inhibitor, has shown potential therapeutic effects in various skeletal disorders. However, the therapeutic implications of NEC1 in TMJ-OA, particularly regarding its effect on chondrocyte senescence, remain unclear. In this study, models of TMJ-OA were established by utilizing monosodium iodoacetate (MIA) to induce TMJ-OA in rats. NEC1 was administered via intra-articular injection. Treatment with NEC1 significantly alleviated the progression of TMJ-OA in rats, reduced pain, and restored cartilage integrity. <i>In vitro</i>, NEC1 (40 μM) exhibited cytoprotective effects on Rat primary condylar chondrocytes (rPCCs), preserving cell viability and reducing cellular senescence markers (Cdkn1a and Cdkn2a) following IL-1β+TNF-α treatment. Additionally, NEC1 inhibited the expression of extracellular matrix (ECM) degradation markers (MMP3, MMP9, MMP13) and programmed necrosis indicators (p-MLKL) in chondrocytes. NEC1 downregulated inflammation-induced p53 and MAPK signaling pathways in rPCCs.Thus, NEC1 demonstrated a significant capacity to slow the progression of TMJ-OA by inhibiting and alleviating condylar chondrocyte senescence, necrosis, and ECM degradation, suggesting its potential role in the treatment of TMJ-OA.