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The Induction of Cell Death in Human Osteoarthritis Chondrocytes by Nitric Oxide Is Related to the Production of Prostaglandin E₂ Via the Induction of Cyclooxygenase-2

Unité de Recherche en Arthrose, Centre Hospitalier de l’Université de Montréal, Hôpital Notre-Dame, Montréal, Québec, Canada

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(OCH₃)-Glu(OCH₃)-Val-Asp(OCH₃)-CH₂F and caspase-9 inhibitor Z-Leu-Glu(OCH₃)-His-Asp(OCH₃)-CH₂F 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 PGE₂ release. PD98059 and SB202190, but neither Z-DEVD FMK nor Z-LEHD FMK completely inhibited the SNP-mediated PGE₂ production. Analysis of interactions between PGE₂ and the cell death showed that PGE₂ enhanced the SNP-mediated cell death, whereas PGE₂ alone did not induce the chondrocyte death. These data indicate that NO-induced chondrocyte death signaling includes PGE₂ 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 PGE₂ production. The results also demonstrate that exogenous PGE₂ may sensitize human OA chondrocytes to the cell death induced by NO.

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