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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Divergent responses of chondrocytes and endothelial cells to shear stress: Cross-talk among COX-2, the phase 2 response, and apoptosis
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Divergent responses of chondrocytes and endothelial cells to shear stress: Cross-talk among COX-2, the phase 2 response, and apoptosis

机译：软骨细胞和内皮细胞对切应力的不同反应：COX-2的串扰，2期反应和凋亡

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摘要

Fluid shear exerts anti-inflammatory and anti-apoptotic effects on endothelial cells by inducing the coordinated expression of phase 2 detoxifying and antioxidant genes. In contrast, high shear is pro-apoptotic in chondrocytes and promotes matrix degradation and cartilage destruction. We have analyzed the mechanisms regulating shear-mediated chondrocyte apoptosis by cDNA microarray technology and bioinformatics. We demonstrate that shear-induced cyclooxygenase (COX)-2 suppresses phosphaticlylinositol 3-kinase (P13-K) activity, which represses antioxidant response element (ARE)/NF-E2 related factor 2 (Nrf2)-mediated transcriptional response in human chondrocytes. The resultant decrease in antioxidant capacity of sheared chondrocytes contributes to their apoptosis. Phase 2 inducers, and to a lesser extent COX-2-selective inhibitors, negate the shear-mediated suppression of ARE-driven phase 2 activity and apoptosis. The abrogation of shear-induced COX-2 expression by P13-K activity and/or stimulation of the Nrf2/ARE pathway suggests the existence of P13-K/Nrf2/ARE negative feedback loops that potentially interfere with c-Jun N-terminal kinase 2 activity upstream of COX-2. Reconstructing the signaling network regulating shear-induced chondrocyte apoptosis may provide insights to optimize conditions for culturing artificial cartilage in bioreactors and for developing therapeutic strategies for arthritic disorders.
机译：液体剪切通过诱导2期排毒和抗氧化基因的协同表达，对内皮细胞发挥抗炎和抗凋亡作用。相反，高剪切在软骨细胞中促凋亡，并促进基质降解和软骨破坏。我们已经通过cDNA微阵列技术和生物信息学分析了调节剪切介导的软骨细胞凋亡的机制。我们证明，剪切诱导的环氧合酶（COX）-2抑制了磷脂酰肌醇3-激酶（P13-K）的活性，从而抑制了人类软骨细胞中抗氧化反应元件（ARE）/ NF-E2相关因子2（Nrf2）介导的转录反应。剪切的软骨细胞的抗氧化能力的下降导致其凋亡。 2期诱导物和程度较小的COX-2选择性抑制剂可消除ARE驱动的2期活性和凋亡的剪切介导抑制作用。通过P13-K活性和/或Nrf2 / ARE途径的刺激消除剪切诱导的COX-2表达，表明存在P13-K / Nrf2 / ARE负反馈环，可能会干扰c-Jun N端激酶COX-2上游有2个活动。重建调节剪切诱导的软骨细胞凋亡的信号网络可能为优化在生物反应器中培养人工软骨的条件以及开发关节炎疾病的治疗策略提供见识。

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