Abstract
Apoptosis may play a role in osteoarthritis (OA). Apoptosis can proceed via two different pathways depending on the stimulus. However, both pathways converge upon the effector caspases, caspases‐3 and ‐7. In some systems inhibition of caspases‐3 and ‐7 can prevent apoptosis and may therefore have important therapeutic implications. To confirm this, apoptosis was induced in canine chondrocytes with mitomycin‐c (MMC), either in the presence or absence of the general caspase inhibitor, Z‐VAD FMK, or a specific caspase‐3/7 inhibitor. Z‐VAD FMK prevented MMC induced cell death. In contrast, inhibition of caspases‐3 and ‐7 in the presence of MMC induced morphological changes that could be described as necrotic‐like or paraptotic‐like but did not prevent cell death. The addition of an inhibitor of caspase‐8 or caspase‐9 along with inhibitor of caspase‐3/7 was required to reduce cell death. The morphological changes did not occur in the presence of the caspase‐3/7 inhibitor alone and could be prevented by addition of Z‐VAD FMK. These data lead to the conclusion that, if the apoptotic program cannot be completed, the cells are pushed into a necrotic or other nonapoptotic mode of death which may involve caspase‐8 and/or caspase‐9. © 2005 Wiley‐Liss, Inc.