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The Induction of Cell Death in Human Osteoarthritis Chondrocytes by Nitric Oxide Is Related to the Production of Prostaglandin E sub(2) Via the Induction of Cyclooxygenase-2

There is increasing evidence suggesting that chondrocyte death may contribute to the progression of osteoarthritis (OA). This study focused on the characterization of signaling cascade during NO-induced cell death in human OA chondrocytes. The NO generator, sodium nitroprusside (SNP), promoted chond...

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Published in:The Journal of immunology (1950) 2000-09, Vol.165 (6), p.3402-3410
Main Authors: Notoya, K, Jovanovic, D V, Reboul, P, Martel-Pelletier, J, Mineau, F, Pelletier, J-P
Format: Article
Language:English
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Summary:There is increasing evidence suggesting that chondrocyte death may contribute to the progression of osteoarthritis (OA). This study focused on the characterization of signaling cascade during NO-induced cell death in human OA chondrocytes. The NO generator, sodium nitroprusside (SNP), promoted chondrocyte death in association with DNA fragmentation, caspase-3 activation, and down-regulation of Bcl-2. Both caspase-3 inhibitor Z-Asp(OCH sub(3))-Glu(OCH sub(3))-Val-Asp(OCH sub(3))-CH sub(2)F and caspase-9 inhibitor Z-Leu-Glu(OCH sub(3))-His-Asp(OCH sub(3))-CH sub(2)F prevented the chondrocyte death. Blocking the mitogen-activated protein kinase pathway by the mitogen-activated protein kinase kinase 1/2 inhibitor PD98059 or p38 kinase inhibitor SB202190 also inhibited the SNP-mediated cell death, suggesting possible requirements of both extracellular signal-related protein kinase 1/2 and p38 kinase for the NO-induced cell death. Furthermore, the selective inhibition of cyclooxygenase (COX)-2 by NS-398 or the inhibition of COX-1/COX-2 by indomethacin blocked the SNP-induced cell death. The chondrocyte death induced by SNP was associated with an overexpression of COX-2 protein (as determined by Western blotting) and an increase in PGE sub(2) release. PD98059 and SB202190, but neither Z-DEVD FMK nor Z-LEHD FMK completely inhibited the SNP-mediated PGE sub(2) production. Analysis of interactions between PGE sub(2) and the cell death showed that PGE sub(2) enhanced the SNP-mediated cell death, whereas PGE sub(2) alone did not induce the chondrocyte death. These data indicate that NO-induced chondrocyte death signaling includes PGE sub(2) production via COX-2 induction and suggest that both extracellular signal-related protein kinase 1/2 and p38 kinase pathways are upstream signaling of the PGE sub(2) production. The results also demonstrate that exogenous PGE sub(2) may sensitize human OA chondrocytes to the cell death induced by NO.
ISSN:0022-1767