Blocking of the P2X7 receptor inhibits the activation of the MMP-13 and NF-κB pathways in the cartilage tissue of rats with osteoarthritis

P2X purinoceptor 7 (P2X(7)) receptor (P2X(7)R) is known to play a significant role in inflammation and pain causing diseases, including osteoarthritis (OA). However, the mechanisms of action of P2X(7)R and its role in OA remain unclear. The articular cartilage is the crucial region in which pathological changes occur in OA, involving the dysregulation of degradation and maintenance mechanisms. In this study, we aimed to reveal the molecular mechanisms of action of P2X(7)R in articular cartilage in OA-induced pain and inflammation by using AZD9056, an antagonist of P2X(7)R. We created an animal model of OA by using Wistar rats administered (by intra-articular injection) monosodium iodoacetate (MIA), and the rats with OA were then treated with the P2X(7)R antagonist, AZD9056. We found that treatment with AZD9056 exerted pain-relieving and anti-inflammatory effects. Importantly, we found that the upregulated expression of interleukin (IL)-1 beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), matrix metalloproteinase-13 (MMP-13), substance P (SP) and prostaglandin E-2 (PGE(2)) which was induced by MIA in cartilage tissues was reversed by AZD9056. Western blot analysis was used to examine the expression of inhibitor of nuclear factor-kappa B (NF-kappa B) kinase (IKK)alpha, IKK beta, inhibitor of NF-kappa B (I kappa B)alpha, NF-kappa B p65 and their phosphorylation forms; they were found to be significantly increased in the knee cartilage tissues from rats with OA; however, opposite effects were observed by the injection of AZD9056. These results implied that P2X(7)R was associated with the activation of the NF-kappa B pathway in the development of OA. Our results also revealed that helenalin, an NF-kappa B pathway inhibitor, decreased the expression of P2X(7)R, IL-1 beta, IL-6, TNF-alpha, SP, PGE(2) and MMP-13, which was induced by MIA, in the knee cartilage tissues of rats with OA. On the whole, our findings suggest that P2X(7)R regulates the MMP-13 and NF-kappa B pathways in cartilage tissue and mediate OA-induced pain and inflammation.