It is likely protein inhibitors that persistent spontaneous release of NO is necessary for the protective effect and that peroxynitrite and cyanide contribute to the cytotoxic effect of NO donors. Chondrocyte cell death from NO occurs under conditions where other reactive oxygen species are also generated. Chondrocyte death does not correlate with the amount of NO released by NO donors. Similar to other authors, our results showed that SNP is the least potent in terms of producing exogenous NO in chondrocyte cul ture, although it is the most potent inducer Inhibitors,Modulators,Libraries of chondro cyte death. The amount of NO produced by NOC 12 was 10 fold higher than the NO produced by SNP, but the level of cell death induced was not as profound as that produced by SNP.

As previously shown in our laboratory, Inhibitors,Modulators,Libraries SNP was able to induce formation of apoptotic bodies, which are produced from cells undergoing cell death by apoptosis. However, we observed that NOC 12 increased the hypodiploid nuclei number without forma tion of apoptotic bodies, which is probably related to another type of programmed cell death. Recently it has been proposed that autophagy is another type of pro grammed cell death than happens in the human articular cartilage as well. The increase in the number of hypopliod nuclei and the observation of some morpholo gic changes as vacuole formation seems to relate NOC 12 with autophagy. It is believed unlikely that NO is the sole mediator of SNP induced chondrocyte death and peroxynitrite, a reaction product of NO and superoxide anions, or the primary by products of the decomposition of SNP, such as the cyanide aninon or pentacy anoferrate complex, might contribute to its cytotoxicity.

It is unclear whether chondrocyte apoptosis Inhibitors,Modulators,Libraries is the major mechanism of cartilage degradation or merely a by product of tissue degeneration. Inhibitors,Modulators,Libraries Mitochondria comprise a target of NO and there is accumulating evidence that inhibition of respiration may contribute to the pro apoptotic effect of NO by m alteration, transition pore opening and release of cyto chrome c. There is increasing evidence about the importance of mitochondria in OA pathology. Pre viously, we showed that the activity of the mitochondrial complexes II and III is lower in OA than in normal human chondrocytes, this produces a decrease in ATP levels as well as a higher ROS generation.

The relevance of the MRC inhibition in human chondrocytes is already known, the inhibition of complexes III and V of the MRC induces an inflammatory response, which could be especially relevant in relation to prostaglandin Inhibitors,Modulators,Libraries E2 production via mitochondrial Ca2 exchange, ROS production, and nuclear factor B activation. More recently, Rego and collaborators have found that the predisposition to the development of OA is related to some haplogroups of mitochondrial respira tory genes ATPase of chondrocytes.