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首页> 外文期刊>Drug Design, Development and Therapy >Activation of GPR40 Suppresses AGE-Induced Reduction of Type II Collagen and Aggrecan in Human SW1353 Chondrocytes
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Activation of GPR40 Suppresses AGE-Induced Reduction of Type II Collagen and Aggrecan in Human SW1353 Chondrocytes

机译：GPR40的激活抑制人SW1353软骨细胞中II型胶原蛋白和蛋白酶的年龄诱导的减少

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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.
机译：简介：骨关节炎（OA）是一种与年龄相关的慢性退行性疾病。晚期糖化末端产物（年龄）的积累诱导关节细胞外基质（ECM）的劣化，并被认为是朝向OA的开发和进展的关键步骤。 GPR40是一种众所周知的游离脂肪酸受体，其在不同类型的疾病中具有脂肪效应。然而，OA中GPR40的生物学功能是模糊的。本研究的目的是确定GPR40激动剂GW9508对经过治疗的软骨细胞的影响。材料和方法：用GW9508刺激人SW1353软骨细胞的培养物，然后暴露于100μg/ ml时代。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Western印迹分析测量II型胶原蛋白，蛋白和核NF-κBp65的水平。荧光素酶测定法测量了NF-κB的转录活性。结果：结果表明，随着年龄的治疗降低了人SW1353软骨细胞的GPR40的表达。通过衰减MMP-3，MMP-13，ADAMTS-4和Adamts-5的表达，GW9508的治疗在保护II型胶原蛋白和骨髓免受退化中起作用。另外，GW9508降低了促炎细胞因子的外观，抑制了诱导的软骨细胞中的NF-κB活化。值得注意的是，与GPR40的特异性拮抗剂的GW1100共同治疗废除了GW9508对年龄的有益作用，这意味着GPR40介导GW9508的这些效果。结论：我们的研究结果表明，GPR40是OA的新疗法靶标，GPR40激动剂包括GW9508，可能具有预防和减缓OA进展的治疗潜力。

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