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

Abstract

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.

The antioxidant resveratrol protects against chondrocyte apoptosis via effects on mitochondrial polarization and ATP production

“…Increased apoptosis has been observed in chondrocytes treated with exogenous PGE 2 and is coupled with increased cAMP (46,47); however, effects on mitochondria have not been reported. Conversely, PGE 2 has been shown to mediate apoptotic resistance in other cell types, including cancer cells (48,49) and gastric mucosal cells (50) via mitochondrion-dependent pathways.…”

Heme oxygenase-1 induction modulates microsomal prostaglandin E synthase-1 expression and prostaglandin E2 production in osteoarthritic chondrocytes

“…In contrast, low concentrations of PGE 2 may downregulate collagenases and collagen 2A1 cleavage [38]. PGE 2 may enhance chondrocyte death [39] and induce apoptosis in bovine articular chondrocytes through the cAMP pathway [40]. In this study, we investigated the effects of HO-1 induction on IL-1-stimulated PGE 2 production in primary OA chondrocytes.…”

Cilostazol protects rat chondrocytes against nitric oxide–induced apoptosis in vitro and prevents cartilage destruction in a rat model of osteoarthritis

“…It is produced in chondrocytes by the action of proinflammatory cytokines such as interleukin-1␤. NO production in chondrocytes causes activation of matrix metalloproteinases (MMPs), decreased production of interleukin-1␤ receptor antagonist, inhibition of proteoglycan synthesis and type II collagen expression, and apoptosis of chondrocytes (2,13,14). Cilostazol, 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy]-3,4-dihydro-2-(1H)-quinolinone, is a potent selective phosphodiesterase type III (PDE III) inhibitor.…”