Osteoarthritis (OA) is one of the most prevalent degenerative joint diseases, and the risk of developing OA significantly increases with age as well as with concomitant diseases, such as diabetes. Advanced glycation end products (AGEs) accumulate in the body over time and are associated with increased expression of various molecules involved in the pathophysiology of OA. Prostaglandin E2 (PGE2), along with its precursor cyclooxygenase (COX)-2, plays an integral role in the pathogenesis of OA and is highly upregulated in response to AGEs. The most significant event in OA is excessive degradation of the cartilage extracellular matrix, which is composed primarily of type II collagen and aggrecan. In the present study, we investigated the involvement of the receptor for glucagon-like peptide (GLP)-1 in the response of chondrocytes to insult from AGEs using the selective GLP-1 agonist dulaglutide. Firstly, our results indicate that AGEs reduced the expression of the receptor for GLP-1 (GLP-1R) in human SW1353 chondrocytes. Interestingly, we found that treatment with dulaglutide could ameliorate deterioration of the components of the articular extracellular matrix (ECM), such as type II collagen and aggrecan, induced by AGEs through downregulation of matrix metalloproteinase (MMP)-3 and MMP-13 and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5. We also found that dulaglutide exerted a potent inhibitory effect against the expression of several proinflammatory cytokines and chemokines closely associated with OA, as well as the production of reactive oxygen species (ROS). Finally, we showed that the effects of dulaglutide were mediated through the nuclear factor kappa-B (NF-κB) pathway. Our findings indicate that dulaglutide displayed a robust protective effect against AGEs-induced damage in chondrocytes, suggesting that it might be a possible therapeutic agent for the treatment of OA.

中文翻译：

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杜拉鲁肽对晚期糖基化终产物（AGEs）诱导的人SW1353软骨细胞中Ⅱ型胶原蛋白和聚集蛋白聚糖降解的保护作用。

骨关节炎（OA）是最普遍的退化性关节疾病之一，发展OA的风险会随着年龄以及伴随疾病（例如糖尿病）而大大增加。晚期糖基化终产物（AGEs）随时间在体内积累，并与OA病理生理学中涉及的各种分子的表达增加有关。前列腺素E2（PGE2）及其前体环氧合酶（COX）-2在OA的发病机理中起着不可或缺的作用，并且对AGEs的反应高度上调。OA中最重要的事件是软骨细胞外基质的过度降解，其主要由II型胶原蛋白和蛋白聚糖组成。在目前的研究中，我们使用选择性GLP-1激动剂dulaglutide研究了胰高血糖素样肽（GLP）-1受体参与软骨细胞对AGEs侵害的反应。首先，我们的结果表明AGEs减少了人SW1353软骨细胞中GLP-1受体（GLP-1R）的表达。有趣的是，我们发现用度拉鲁肽治疗可以减轻AGEs通过下调基质金属蛋白酶（MMP）-3和MMP-13和a引起的关节细胞外基质（ECM）成分（如II型胶原蛋白和聚集蛋白聚糖）的降解。带有血小板反应蛋白基序（ADAMTS）-4和ADAMTS-5的双整合蛋白和金属蛋白酶。我们还发现，度拉鲁肽对与OA密切相关的几种促炎性细胞因子和趋化因子的表达具有有效的抑制作用，以及活性氧（ROS）的产生。最后，我们证明了dulaglutide的作用是通过核因子κB（NF-κB）途径介导的。我们的研究结果表明，度拉鲁肽显示出对AGEs诱导的软骨细胞损伤的强大保护作用，表明它可能是治疗OA的可能治疗剂。