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. doi: 10.1073/pnas.0506620102. Epub 2005 Sep 19.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antioxidants / metabolism
  • Apoptosis / genetics*
  • Chondrocytes / drug effects
  • Chondrocytes / enzymology
  • Chondrocytes / metabolism*
  • Cyclooxygenase Inhibitors / pharmacology
  • Endothelial Cells / drug effects
  • Endothelial Cells / enzymology
  • Endothelial Cells / metabolism
  • Humans
  • Isothiocyanates
  • Mitogen-Activated Protein Kinase 9 / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Phosphatidylinositol 3-Kinases / metabolism
  • Response Elements
  • Shear Strength
  • Signal Transduction
  • Stress, Mechanical
  • Thiocyanates / pharmacology
  • Thiones / pharmacology
  • Thiophenes / pharmacology
  • Transcription, Genetic

Substances

  • Antineoplastic Agents
  • Antioxidants
  • Cyclooxygenase Inhibitors
  • Isothiocyanates
  • Thiocyanates
  • Thiones
  • Thiophenes
  • Mitogen-Activated Protein Kinase 9
  • sulforaphane
  • 1,2-dithiol-3-thione