Document Detail


Divergent responses of chondrocytes and endothelial cells to shear stress: cross-talk among COX-2, the phase 2 response, and apoptosis.
MedLine Citation:
PMID:  16172382     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Zachary R Healy; Norman H Lee; Xiangqun Gao; Mary B Goldring; Paul Talalay; Thomas W Kensler; Konstantinos Konstantopoulos
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2005-09-19
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  102     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2005 Sep 
Date Detail:
Created Date:  2005-09-28     Completed Date:  2005-11-21     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  14010-5     Citation Subset:  IM    
Affiliation:
Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA.
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MeSH Terms
Descriptor/Qualifier:
1-Phosphatidylinositol 3-Kinase / metabolism
Antineoplastic Agents / pharmacology
Antioxidants / metabolism
Apoptosis / genetics*
Chondrocytes / drug effects,  enzymology,  metabolism*
Cyclooxygenase Inhibitors / pharmacology
Endothelial Cells / drug effects,  enzymology,  metabolism
Humans
Mitogen-Activated Protein Kinase 9 / metabolism
Oligonucleotide Array Sequence Analysis
Response Elements
Shear Strength
Signal Transduction
Stress, Mechanical
Thiocyanates / pharmacology
Thiones / pharmacology
Thiophenes / pharmacology
Transcription, Genetic
Grant Support
ID/Acronym/Agency:
R01-AG22021/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Antioxidants; 0/Cyclooxygenase Inhibitors; 0/Thiocyanates; 0/Thiones; 0/Thiophenes; 4478-93-7/sulforafan; 534-25-8/1,2-dithiol-3-thione; EC 2.7.1.137/1-Phosphatidylinositol 3-Kinase; EC 2.7.1.24/Mitogen-Activated Protein Kinase 9
Comments/Corrections

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