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

Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 10/2005; 102(39):14010-5. DOI: 10.1073/pnas.0506620102
Source: PubMed

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.

Download full-text


Available from: Konstantinos Konstantopoulos, Aug 25, 2015
  • Source
    • "According to this structure, anthocyanynins are electrophiles, positively charged species that are attracted to an electron rich center [47]. The main dietary sources of anthocyanin are blue and purple fruit, such as berries and grapes [7]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Anthocyanins have been reported to induce the expression of enzymes involved in both cellular antioxidant defenses and attenuating inflammation-associated pathogenesis. Induction of such enzymes by edible anthocyanin largely accounts for their atherosclerosis chemo-protective activities. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays an essential role in the coordinated induction of those genes encoding redox-responsive and cellular defense antioxidant enzyme termed antioxidant response element (ARE). Current studies have revealed that Nrf2-ARE signaling is involved in attenuating inflammation-associated pathogenesis such as atherosclerosis. Conversely, reduction in Nrf2 signaling leads to enhanced susceptibility to oxidative stress and inflammatory tissue injuries. The activation of Nrf2-ARE might inhibit the production of pro-inflammatory mediator including cyclooxygenase-2, chemokines, cytokines, cell adhesion molecules, and induction nitric oxide synthase. This review highlights the gene expression induced by dietary anthocyanin via Nrf2 signaling on redox-regulated transcription factor in atherosclerosis disorders. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    Biomedecine [?] Pharmacotherapy 04/2015; 72. DOI:10.1016/j.biopha.2015.03.008 · 2.11 Impact Factor
  • Source
    • "However, it is also clear that higher or sustained levels of ROS damage a broad variety of molecules including lipids, nucleic acids, and proteins (Blumberg, 2004; Lotz and Loeser, 2012). Release of oxygen and nitrogen radicals, following mechanical cartilage damage by excessive shear stress, have been implicated previously in chondrocyte cell death by several mechanisms including apoptosis and preterm senescence (Healy et al., 2005). Chondrocyte apoptosis is induced directly by ROS and reactive nitrogen species (RNS)-induced cytotoxicity (Blanco et al., 1998; Wu et al., 2007) as well as indirectly by activation of the apoptosis signalregulating kinase (ASK1), which induces c-Jun N-terminal kinases and p38 mitogen-activated protein kinases. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aging-related oxidative stress has been linked to degenerative modifications in different organs and tissues. Using redox proteomic analysis and illustrative tandem mass spectrometry mapping, we demonstrate oxidative posttranslational modifications in structural proteins of intervertebral discs (IVDs) isolated from aging mice. Increased protein carbonylation was associated with protein fragmentation and aggregation. Complementing these findings, a significant loss of elasticity and increased stiffness was measured in fibrocartilage from aging mice. Studies using circular dichroism and intrinsic tryptophan fluorescence revealed a significant loss of secondary and tertiary structures of purified collagens following oxidation. Collagen unfolding and oxidation promoted both nonenzymatic and enzymatic degradation. Importantly, induction of oxidative modification in healthy fibrocartilage recapitulated the biochemical and biophysical modifications observed in the aging IVD. Together, these results suggest that protein carbonylation, glycation, and lipoxidation could be early events in promoting IVD degenerative changes.
    Chemistry & biology 07/2013; 20(7):922-34. DOI:10.1016/j.chembiol.2013.06.006 · 6.59 Impact Factor
  • Source
    • "Upregulation of the inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2) enzymes will lead to several effects in chondrocytes including increased cytokine production, MMP activation, ROS production, and apoptosis [118] [119] [120] [121]. The induction of cell death by fluidinduced shear stress involves protein kinase (PKB) activation and suppression of phosphatidylinositol 3-kinase (PI3-K), which inhibits antioxidant capacity leading to apoptosis [122] [123]. In addition, exposure of T/C-28a2 chondrocytes to high levels of shear stress increased PGE 2 production and IL-6 expression leading to matrix degradation and chondrocyte apoptosis [124] [125]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: There is an urgent demand for long term solutions to improve osteoarthritis treatments in the ageing population. There are drugs that control the pain but none that stop the progression of the disease in a safe and efficient way. Increased intervention efforts, augmented by early diagnosis and integrated biophysical therapies are therefore needed. Unfortunately, progress has been hampered due to the wide variety of experimental models which examine the effect of mechanical stimuli and inflammatory mediators on signal transduction pathways. Our understanding of the early mechanopathophysiology is poor, particularly the way in which mechanical stimuli influences cell function and regulates matrix synthesis. This makes it difficult to identify reliable targets and design new therapies. In addition, the effect of mechanical loading on matrix turnover is dependent on the nature of the mechanical stimulus. Accumulating evidence suggests that moderate mechanical loading helps to maintain cartilage integrity with a low turnover of matrix constituents. In contrast, nonphysiological mechanical signals are associated with increased cartilage damage and degenerative changes. This review will discuss the pathways regulated by compressive loading regimes and inflammatory signals in animal and in vitro 3D models. Identification of the chondroprotective pathways will reveal novel targets for osteoarthritis treatments.
    09/2011; 2011:979032. DOI:10.1155/2011/979032
Show more