Osteoarthritis (OA) is one of the most common degenerative joint diseases in aging people. The activation of chondrocytes and their dysregulation are closely related to the pathogenesis of OA. GPR55 is an unique orphan G-receptor which binds to cannabinoids. In this study, we explored the role of GPR55 in advanced glycation end productions (AGEs)- induced chondrocytes activation in cultured cells. We showed that AGEs dose dependently induced GPR55 expression in ATDC5 chondrocytes. The blockage of GPR55 by its newly discovered antagonist-CID16020046 mitigated AGEs- induced increase in cellular ROS and decrease in antioxidant NRF2. Moreover, CID16020046 showed a dose-response suppressive effect on AGEs- induced expression of the major inflammatory mediators, including COX-2 and iNOS, and the production of NO and PGE2. CID16020046 also dose responsively inhibited AGEs- induced key effectors of cartilage degradation such as MMP-3 and MMP-13. In consequence, CID16020046 showed robust inhibition on AGEs- induced type II collagen degradation. Mechanistically, our data demonstrated that CID16020046 mediated GPR55 blockage ameliorated AGEs- induced NF-κB activation as revealed by its inhibition on IκBα, nuclear p65 translocation and NF-κB promoter activity. Collectively, our study demonstrates that GPR55 signaling mediates AGEs- induced chondrocyte activation, and the targeted blockage of GPR55 pathway could be therapeutic choice in the treatment of osteoarthritis.

中文翻译：

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GPR55拮抗剂CID16020046可减轻晚期糖基化终产物（AGEs）诱导的软骨细胞活化。

骨关节炎（OA）是老年人中最常见的变性关节疾病之一。软骨细胞的活化及其失调与OA的发病机制密切相关。GPR55是与大麻素结合的独特的孤儿G受体。在这项研究中，我们探讨了GPR55在晚期糖基化终末产物（AGEs）诱导的培养细胞软骨细胞活化中的作用。我们显示，AGEs剂量依赖性地诱导ATDC5软骨细胞中GPR55的表达。GPR55被新发现的拮抗剂CID16020046阻滞减轻了AGEs诱导的细胞ROS的增加和抗氧化剂NRF2的减少。此外，CID16020046对AGEs诱导的主要炎症介质（包括COX-2和iNOS）的表达以及NO和PGE2的产生具有剂量反应抑制作用。CID16020046还可以剂量反应性抑制AGEs诱导的软骨降解关键效应物，如MMP-3和MMP-13。因此，CID16020046对AGEs诱导的II型胶原蛋白降解显示出强大的抑制作用。从机理上讲，我们的数据表明，CID16020046介导的GPR55阻滞改善了AGEs诱导的NF-κB活化，如其对IκBα，核p65易位和NF-κB启动子活性的抑制所揭示。总体而言，我们的研究表明，GPR55信号传导介导AGEs诱导的软骨细胞活化，并且靶向阻断GPR55途径可能是治疗骨关节炎的治疗选择。从机理上讲，我们的数据表明，CID16020046介导的GPR55阻滞改善了AGEs诱导的NF-κB活化，如其对IκBα，核p65易位和NF-κB启动子活性的抑制所揭示。总体而言，我们的研究表明，GPR55信号传导介导AGEs诱导的软骨细胞活化，并且靶向阻断GPR55途径可能是治疗骨关节炎的治疗选择。从机理上讲，我们的数据表明，CID16020046介导的GPR55阻滞改善了AGEs诱导的NF-κB活化，如其对IκBα，核p65易位和NF-κB启动子活性的抑制所揭示。总体而言，我们的研究表明，GPR55信号传导介导AGEs诱导的软骨细胞活化，并且靶向阻断GPR55途径可能是治疗骨关节炎的治疗选择。