Introduction: Osteoarthritis (OA) is an age-related chronic degenerative disease. Accumulation of advanced glycation end products (AGEs) induces degradation of the articular extracellular matrix (ECM) and is considered a critical step toward the development and progression of OA. GPR40 is a well-known free fatty acid receptor, which possesses pleiotropic effects in different types of diseases. However, the biological function of GPR40 in OA is indistinct. The purpose of the present study was to determine the impact of the GPR40 agonist GW9508 on AGEs-treated chondrocytes.
Materials and Methods: Cultures of human SW1353 chondrocytes were stimulated with GW9508, followed by exposure to 100 μg/mL AGEs. Gene and protein expression of TNF-α, IL-6, MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5 were measured by real-time PCR and ELISA analysis. The levels of type II collagen, aggrecan, and nuclear NF-κB p65 were measured by Western blot analysis. A luciferase assay measured the transcriptional activity of NF-κB.
Results: The results show that treatment with AGEs decreased the expression of GPR40 in human SW1353 chondrocytes. Treatment with GW9508 plays a beneficial role in protecting type II Collagen and aggrecan from degeneration by attenuating the expression of MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5. Additionally, GW9508 reduces the appearance of pro-inflammatory cytokines and suppresses NF-κB activation in AGEs-induced chondrocytes. Notably, co-treatment with GW1100, a specific antagonist of GPR40, abolishes the beneficial role of GW9508 against AGEs, implying that GPR40 mediates these effects of GW9508.
Conclusion: Our results suggest that GPR40 is a novel therapeutic target for OA and that GPR40 agonists, including GW9508, may have therapeutic potential in preventing and slowing the progression of OA.

Keywords: osteoarthritis, GPR40, GW9508, MMPs, ADAMTS, NF-κB


中文翻译：

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GPR40 的激活抑制 AGE 诱导的人 SW1353 软骨细胞中 II 型胶原蛋白和聚集蛋白聚糖的减少。

简介：骨关节炎（OA）是一种与年龄相关的慢性退行性疾病。晚期糖基化终产物 (AGEs) 的积累会诱导关节细胞外基质 (ECM) 的降解，并被认为是 OA 发展和进展的关键步骤。GPR40是一种众所周知的游离脂肪酸受体，在不同类型的疾病中具有多效性。然而，GPR40 在 OA 中的生物学功能尚不明确。本研究的目的是确定 GPR40 激动剂 GW9508 对 AGEs 处理的软骨细胞的影响。
材料和方法：用 GW9508 刺激人 SW1353 软骨细胞的培养物，然后暴露于 100 μg/mL AGEs。通过实时 PCR 和 ELISA 分析测量 TNF-α、IL-6、MMP-3、MMP-13、ADAMTS-4 和 ADAMTS-5 的基因和蛋白质表达。通过蛋白质印迹分析测量 II 型胶原蛋白、聚集蛋白聚糖和核 NF-κB p65 的水平。荧光素酶测定测量了 NF-κB 的转录活性。
结果：结果表明，AGEs 处理降低了人 SW1353 软骨细胞中 GPR40 的表达。GW9508 治疗通过减弱 MMP-3、MMP-13、ADAMTS-4 和 ADAMTS-5 的表达，在保护 II 型胶原蛋白和聚集蛋白聚糖免于变性方面发挥有益作用。此外，GW9508 减少促炎细胞因子的出现并抑制 AGEs 诱导的软骨细胞中的 NF-κB 活化。值得注意的是，与 GPR40 的特异性拮抗剂 GW1100 共同治疗，消除了 GW9508 对 AGEs 的有益作用，这意味着 GPR40 介导了 GW9508 的这些作用。
结论：我们的研究结果表明，GPR40 是一种新的 OA 治疗靶点，包括 GW9508 在内的 GPR40 激动剂可能具有预防和减缓 OA 进展的治疗潜力。

关键词：骨关节炎, GPR40, GW9508, MMPs, ADAMTS, NF-κB