Caspase-3/7 inhibition alters cell morphology in mitomycin-C treated chondrocytes.
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.
Clements
Kristen M
KM
Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA.
Burton-Wurster
Nancy
N
Nuttall
Mark E
ME
Lust
George
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D053179:Caspase 7; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D046529:Microscopy, Electron, Transmission; D016685:Mitomycin / Q000494:pharmacology*; D010641:Phenotype
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D016685:Mitomycin; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases