Journal
BIOCHEMICAL PHARMACOLOGY
Volume 77, Issue 12, Pages 1806-1813Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2009.03.009
Keywords
Heme oxygenase-1; Chondrocyte; Osteoarthritis; Interleukin-1 beta; Prostaglandin E-2; Microsomal PGE synthase-1
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Funding
- Spanish Ministerio de Educacion y Ciencia
- Generalitat Valenciana
- [SAF2007-61769]
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Pro-inflammatory cytokines such as interleukin-1 beta (IL-1 beta) may participate in the pathogenesis of cartilage damage in osteoarthritis (OA) through the production of catabolic enzymes and inflammatory mediators. Induction of heme oxygenase-1 (HO-1) has previously been shown to exert anti-inflammatory effects in different cell types. We have investigated whether HO-1 induction may modify chondrocyte viability and the production of relevant mediators such as oxidative stress and prostaglandin E-2 (PGE(2)) elicited by IL-1 beta in OA chondrocytes. Chondrocytes were isolated from OA cartilage and used in primary culture. Cells were stimulated with IL-1 beta in the absence or presence of the HO-1 inducer cobalt protoporphyrin IX (CoPP). Gene expression was assessed by quantitative real-time PCR, protein levels by ELISA and Western blot, apoptosis by laser scanning cytometry using annexin V-FITC and TUNEL assays, and oxidative stress by LSC with dihydrorhodamine 123. HO-1 induction by CoPP enhanced chondrocyte viability and aggrecan content while inhibiting apoptosis and oxidative stress generation. PGE(2) is produced in OA chondrocytes stimulated by IL-1 beta by the coordinated induction of cyclooxygenase-2 and microsomal PGE synthase 1 (mPGES- 1). The production of PGE(2) was decreased by HO-1 induction as a result of diminished mPGES-1 protein and mRNA expression. Transfection with HO-1 small interfering RNA counteracted CoPP effects. in addition, the activation of nuclear factor-kappa B and early growth response-1 was significantly reduced by CoPP providing a basis for its anti-inflammatory effects. These results confirm the protective role of HO-1 induction in OA chondrocytes and suggest the potential interest of this strategy in degenerative joint diseases. (c) 2009 Elsevier Inc. All rights reserved.
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