BACKGROUND Progression of osteoarthritis (OA) is characterized by an excessive production of matrix degrading enzymes and insufficient matrix repair. Despite of active research in this area, it is still unclear how the combination of mechanical exposure and drug therapy works. This study was done to explore the impact of the disease modifying OA drug (DMOAD) diacerein and moderate tensile strain on the anabolic metabolism and the integrin-FAK-MAPKs signal transduction cascade of OA and non-OA chondrocytes. METHODS Cyclic tensile strain was applied in terms of three different intensities by the Flexcell tension system. Influence on catabolic parameters such as MMPs, ADAMTS, and IL-6 were assessed by qPCR. Changes in phosphorylation of FAK, STAT3 as well as MAP kinases were verified by western blot analysis. Intracellular calcium was measured fluorimetrically using fura-2. RESULTS Tensile strain at moderate intensity (SM/SA profile) proved to be most efficient in terms of reducing production of matrix degrading enzyme and IL-6 expression. Treatment with diacerein by itself and diacerein in combination with SM/SA stimulation reduced phosphorylation of FAK and STAT3, which is more pronounced in OA cells. Pretreatment with diacerein for 7 days resulted in an increase in the sensitivity to Yoda1, the agonist for the mechanically activated ion channel Piezo1. However, in OA chondrocytes a significant reduction in Piezo1 expression was observed following treatment with diacerein. CONCLUSION Our results demonstrated for the first time that diacerein intensively intervenes in the regulation of FAK and STAT3 and influences components considered relevant for the progression of OA, even in the presence of mechanical stimulation.

中文翻译：

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机械暴露和双醋瑞因治疗可调节人骨关节炎软骨细胞中的整合素-FAK-MAPKs 机械转导。

背景技术骨关节炎(OA)的进展以基质降解酶的过量产生和基质修复不足为特征。尽管在这一领域进行了积极的研究，但仍不清楚机械暴露和药物治疗的结合如何发挥作用。本研究旨在探讨改善疾病的 OA 药物 (DMOAD) 双醋瑞因和中度拉伸应变对 OA 和非 OA 软骨细胞的合成代谢和整合素-FAK-MAPKs 信号转导级联的影响。方法 循环拉伸应变通过 Flexcell 张力系统以三种不同的强度施加。通过 qPCR 评估对分解代谢参数（如 MMP、ADAMTS 和 IL-6）的影响。通过蛋白质印迹分析验证了 FAK、STAT3 以及 MAP 激酶的磷酸化变化。使用 fura-2 荧光法测量细胞内钙。结果 中等强度的拉伸应变（SM/SA 曲线）在减少基质降解酶的产生和 IL-6 表达方面被证明是最有效的。双醋瑞因本身和双醋瑞因联合 SM/SA 刺激处理可降低 FAK 和 STAT3 的磷酸化，这在 OA 细胞中更为明显。用双醋瑞因预处理 7 天导致对 Yoda1 的敏感性增加，Yoda1 是机械激活离子通道 Piezo1 的激动剂。然而，在用双醋瑞因处理后，在 OA 软骨细胞中观察到 Piezo1 表达显着降低。