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Caspase-3/7 inhibition alters cell morphology in mitomycin-C treated chondrocytes
Kristen M Clements1, Nancy Burton-Wurster, Mark E Nuttall
1Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA.
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.
Insights
In osteoarthritis, blocking caspases-3 and -7 alone did not prevent cell death but caused necrotic changes. Complete cell death prevention required inhibiting caspase-8 or -9 alongside caspases-3/7.
Area of Science:
- Cell Biology
- Biochemistry
Background:
- Apoptosis, or programmed cell death, is implicated in osteoarthritis (OA) pathogenesis.
- Apoptosis can occur through multiple pathways, converging on effector caspases-3 and -7.
- Inhibiting caspases-3 and -7 may offer therapeutic benefits in OA by preventing cell death.
Purpose of the Study:
- To investigate the role of effector caspases in mediating apoptosis and cell death in canine chondrocytes.
- To determine if inhibiting caspases-3 and -7 can prevent mitomycin-c (MMC)-induced cell death in chondrocytes.
- To explore the consequences of incomplete apoptosis and alternative cell death pathways.
Main Methods:
- Apoptosis was induced in canine chondrocytes using mitomycin-c (MMC).
- Cells were treated with a general caspase inhibitor (Z-VAD FMK) or specific inhibitors for caspases-3/7, caspase-8, or caspase-9.
- Morphological changes and cell viability were assessed to differentiate between apoptosis, necrosis, and paraptosis.
Main Results:
- The general caspase inhibitor Z-VAD FMK effectively prevented MMC-induced chondrocyte death.
- Inhibition of caspases-3 and -7 alone did not prevent cell death but induced necrotic-like or paraptotic-like morphological changes.
- Preventing cell death required the additional inhibition of caspase-8 or caspase-9 when caspases-3/7 were also inhibited.
Conclusions:
- Incomplete apoptosis in chondrocytes can lead to alternative cell death pathways, such as necrosis or paraptosis.
- Caspase-8 and/or caspase-9 may play critical roles in non-apoptotic cell death when the apoptotic program is blocked.
- Targeting specific caspase pathways may be crucial for managing cell death in osteoarthritis, considering the potential for alternative death modes.
