JCVI: 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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Healy, Z. R., Lee, N. H., Gao, X., Goldring, M. B., Talalay, P., Kensler, T. W., Konstantopoulos, K.

Divergent Responses of Chondrocytes and Endothelial Cells to Shear Stress: Cross-talk Among COX-2, the Phase 2 Response, and Apoptosis

Proc Natl Acad Sci U S A. 2005 Sep 27; 102(39): 14010-5.

PubMed Citation

Abstract

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 phosphatidylinositol 3-kinase (PI3-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 PI3-K activity and/or stimulation of the Nrf2/ARE pathway suggests the existence of PI3-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.