Divergent responses of chondrocytes and endothelial cells to shear stress: cross-talk among COX-2, the phase 2 response, and apoptosis.
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.
Healy
Zachary R
ZR
Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA.
Lee
Norman H
NH
Gao
Xiangqun
X
Goldring
Mary B
MB
Talalay
Paul
P
Kensler
Thomas W
TW
Konstantopoulos
Konstantinos
K
D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics*; D019902:Chondrocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020218:Response Elements; D033081:Shear Strength; D015398:Signal Transduction; D013314:Stress, Mechanical; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology; D013871:Thiones / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014158:Transcription, Genetic
D000970:Antineoplastic Agents; D000975:Antioxidants; D016861:Cyclooxygenase Inhibitors; D017879:Isothiocyanates; D048056:Mitogen-Activated Protein Kinase 9; D019869:Phosphatidylinositol 3-Kinases; D013454:Sulfoxides; D013861:Thiocyanates; D013871:Thiones; D013876:Thiophenes; C016766:sulforaphane; C049325:1,2-dithiol-3-thione