Clements Kristen M, Burton-Wurster Nancy, Nuttall Mark E, Lust George
Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA.
J Cell Physiol. 2005 Oct;205(1):133-40. doi: 10.1002/jcp.20373.
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.
细胞凋亡可能在骨关节炎（OA）中发挥作用。根据刺激因素的不同，细胞凋亡可通过两条不同的途径进行。然而，这两条途径最终都会汇聚到效应半胱天冬酶，即半胱天冬酶-3和-7。在某些系统中，抑制半胱天冬酶-3和-7可阻止细胞凋亡，因此可能具有重要的治疗意义。为了证实这一点，在有或没有通用半胱天冬酶抑制剂Z-VAD FMK或特异性半胱天冬酶-3/7抑制剂的情况下，用丝裂霉素-C（MMC）诱导犬软骨细胞发生凋亡。Z-VAD FMK可防止MMC诱导的细胞死亡。相比之下，在MMC存在的情况下抑制半胱天冬酶-3和-7会诱导形态学变化，这种变化可被描述为坏死样或类副凋亡样，但并不能阻止细胞死亡。需要同时添加半胱天冬酶-8或半胱天冬酶-9抑制剂以及半胱天冬酶-3/7抑制剂才能减少细胞死亡。单独使用半胱天冬酶-3/7抑制剂时不会出现形态学变化，添加Z-VAD FMK可防止这种变化。这些数据得出的结论是，如果凋亡程序无法完成，细胞会被推向坏死或其他非凋亡性死亡模式，这可能涉及半胱天冬酶-8和/或半胱天冬酶-9。
