title: Blocking of the P2X7 receptor inhibits the activation of the MMP-13 and NF-κB pathways in the cartilage tissue of rats with osteoarthritis.
abstract: P2X purinoceptor 7 (P2X7) receptor (P2X7R) is known to play a significant role in inflammation and pain-causing diseases, including osteoarthritis (OA). However, the mechanisms of action of P2X7R 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 P2X7R in articular cartilage in OA-induced pain and inflammation by using AZD9056, an antagonist of P2X7R. 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 P2X7R 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)-1β, IL-6, tumor necrosis factor-α (TNF-α), matrix metalloproteinase-13 (MMP-13), substance P (SP) and prostaglandin E2 (PGE2) 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-κB (NF-κB) kinase (IKK)α, IKKβ, inhibitor of NF-κB (IκB)α, NF-κB 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 P2X7R was associated with the activation of the NF-κB pathway in the development of OA. Our results also revealed that helenalin, an NF-κB pathway inhibitor, decreased the expression of P2X7R, IL-1β, IL-6, TNF-α, SP, PGE2 and MMP-13, which was induced by MIA, in the knee cartilage tissues of rats with OA. On the whole, our findings suggest that P2X7R regulates the MMP-13 and NF-κB pathways in cartilage tissue and mediate OA-induced pain and inflammation.
authors.affiliation: Second Department of Orthopaedics, Weinan Central Hospital, Weinan, Shaanxi 714000, P.R. China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Οrthopaedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Baohui
authors.initials: B
authors.lastname: Yang
authors.affiliation: Second Department of Orthopaedics, Weinan Central Hospital, Weinan, Shaanxi 714000, P.R. China.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Second Department of Orthopaedics, Weinan Central Hospital, Weinan, Shaanxi 714000, P.R. China.
authors.forename: Subin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Second Department of Orthopaedics, Weinan Central Hospital, Weinan, Shaanxi 714000, P.R. China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D015415:Biomarkers; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D007719:Knee Joint / Q000378:metabolism / Q000473:pathology; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010003:Osteoarthritis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D051381:Rats; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology; D045789:Sesquiterpenes, Guaiane; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D016328:NF-kappa B; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; C001329:helenalin; D053509:Matrix Metalloproteinase 13; D015232:Dinoprostone