16172382

pubmed:Citation

39

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.

http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-10716996, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-10997270, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-11180282, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-11274155, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-11585835, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-11752465, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-11911832, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-12032331, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-12370194, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-12506115, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-12743126, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-12832036, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-12938158, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-12960175, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-14555211, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-14764894, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-14764898, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-15032691, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-15242986, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-15280586, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-15480079, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-15480081, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-15750045, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-15767573, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-15917255, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-7701328, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-8107826, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-8980122, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-9021924, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-9077531, http://linkedlifedata.com/resource/pubmed/commentcorrection/16172382-9751096

http://linkedlifedata.com/resource/pubmed/journal/7505876

http://linkedlifedata.com/resource/pubmed/chemical/1,2-dithiol-3-thione, http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, http://linkedlifedata.com/resource/pubmed/chemical/Antioxidants, http://linkedlifedata.com/resource/pubmed/chemical/Cyclooxygenase Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase 9, http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases, http://linkedlifedata.com/resource/pubmed/chemical/Thiocyanates, http://linkedlifedata.com/resource/pubmed/chemical/Thiones, http://linkedlifedata.com/resource/pubmed/chemical/Thiophenes, http://linkedlifedata.com/resource/pubmed/chemical/sulforafan

Sep

pubmed-author:GaoXiangqunX, pubmed-author:GoldringMary BMB, pubmed-author:HealyZachary RZR, pubmed-author:KenslerThomas WTW, pubmed-author:KonstantopoulosKonstantinosK, pubmed-author:LeeNorman HNH, pubmed-author:TalalayPaulP

27

NLM

14010-5

pubmed-meshheading:16172382-Antineoplastic Agents, pubmed-meshheading:16172382-Antioxidants, pubmed-meshheading:16172382-Apoptosis, pubmed-meshheading:16172382-Chondrocytes, pubmed-meshheading:16172382-Cyclooxygenase Inhibitors, pubmed-meshheading:16172382-Endothelial Cells, pubmed-meshheading:16172382-Humans, pubmed-meshheading:16172382-Mitogen-Activated Protein Kinase 9, pubmed-meshheading:16172382-Oligonucleotide Array Sequence Analysis, pubmed-meshheading:16172382-Phosphatidylinositol 3-Kinases, pubmed-meshheading:16172382-Response Elements, pubmed-meshheading:16172382-Shear Strength, pubmed-meshheading:16172382-Signal Transduction, pubmed-meshheading:16172382-Stress, Mechanical, pubmed-meshheading:16172382-Thiocyanates, pubmed-meshheading:16172382-Thiones, pubmed-meshheading:16172382-Thiophenes, pubmed-meshheading:16172382-Transcription, Genetic

Divergent responses of chondrocytes and endothelial cells to shear stress: cross-talk among COX-2, the phase 2 response, and apoptosis.

Journal Article, Research Support, U.S. Gov't, P.H.S.