Increased Expression of Connexin 43 Promotes Wnt/β-Catenin Signaling and the Progression of Temporomandibular Joint Osteoarthritis.

Temporomandibular joint osteoarthritis (TMJOA) is a prevalent disorder featuring abnormal occlusion and oxidative stress (OS) as key pathogenic factors. TMJOA progression is accompanied by significant activation of the Wnt/β-catenin signaling pathway. Connexin 43 (Cx43), which shapes a dynamic protein network central to OA pathogenesis, may interact with Wnt pathway members within a complex regulatory framework. However, the changes in Cx43 expression in condylar cartilage under OS, along with the crosstalk between Cx43 and Wnt pathway members in the context of TMJOA, remain poorly understood. Here, we aimed to investigate the expression and function of Cx43 in TMJOA, particularly its interplay with Wnt/β-catenin signaling. We investigated TMJOA progression using an in vivo unilateral anterior crossbite (UAC) model of malocclusion and an in vitro model in which isolated chondrocytes were treated with H₂O₂ to induce OS. The functions of Cx43 were further probed through the administration of its specific inhibitor, Gap26. UAC induced OA-like degeneration in the rat TMJ, along with upregulation of Cx43 expression and activation of the Wnt/β-catenin pathway in condylar cartilage. In chondrocytes, H₂O₂ triggered OS and extracellular matrix degradation and increased the expression of β-catenin and membrane-localized Cx43. Direct protein-protein interactions between Cx43 and β-catenin were confirmed by coimmunoprecipitation. Gap26 effectively reduced hemichannel opening, suppressed Wnt/β-catenin signaling, and mitigated degenerative changes in both cellular and animal models. These results indicate that targeting the Cx43-Wnt/β-catenin signaling axis may offer a potential therapeutic strategy for treating TMJOA.