Beneficial effects of intra-articular caspase inhibition therapy following osteochondral injury
Beneficial effects of intra-articular caspase inhibition therapy following osteochondral injury
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DOI：
10.1016/j.joca.2005.12.010
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发表时间：
2006-06-01
影响因子：
7
通讯作者：
Kim, H. T.
中科院分区：
文献类型：
--
作者：
Dang, A. C.;Warren, A. P.;Kim, H. T.
目的：最近的研究表明，关节软骨损伤通过一种称为“细胞凋亡”或程序性细胞死亡（PCD）的机制导致软骨细胞死亡。半胱天冬酶抑制剂是细胞凋亡的关键酶介体，已被证明可以阻断软骨细胞 PCD。我们假设短期关节内给予强效半胱天冬酶抑制剂会减少兔子实验性骨软骨损伤后的软骨细胞PCD和随后的软骨退化。方法：成年新西兰白兔的股骨髁骨软骨损伤。治疗组的膝盖每天接受广谱 caspase 抑制剂 Z-VAD-fmk 的关节内注射，持续 7 天，而对照组仅接受媒介物注射。损伤后 7 天，处死一组兔子以评估软骨细胞 PCD 水平。第二组在受伤后 42 天处死进行组织学评估，以测量软骨变性和软骨修复。结果：受伤后 7 天，与对照组相比，经过 caspase 抑制剂治疗的膝盖中软骨细胞 PCD 减少了 45%（P = 0.01）。受伤后 42 天，经过治疗的膝盖软骨细胞存活率增加了 17.9%（P < 0.01），关节软骨厚度增加了 7.6%（P = 0.01）。 结论：在该模型中实验性骨软骨损伤后，关节内给予 caspase 抑制剂 Z-VAD-fmk 可有效阻断软骨细胞 PCD。抑制软骨细胞 PCD 可挽救否则会死亡的软骨细胞，从而限制随后的软骨损失。据我们所知，这项研究首次证明短期抑制软骨细胞PCD可导致体内软骨的长期保存。 (c) 2006 年国际骨关节炎研究协会。由爱思唯尔有限公司出版。保留所有权利。
Objective: Recent studies have demonstrated that articular cartilage injury leads to chondrocyte death through a mechanism termed "apoptosis", or programmed cell death (PCD). Inhibitors of caspases, key enzymatic mediators of apoptosis, have been shown to block chondrocyte PCD. We hypothesized that short-term intra-articular administration of a potent caspase inhibitor would decrease chondrocyte PCD and subsequent cartilage degeneration following experimental osteochondral injury in rabbits.Methods: Adult New Zealand white rabbits were subjected to osteochondral injuries of their femoral condyles. Knees in the treatment group received daily intra-articular injections of the broad-spectrum caspase inhibitor Z-VAD-fmk for 7 days, while the control group received injections of Vehicle alone. Seven days postinjury, one group of rabbits was sacrificed to assess levels of chondrocyte PCD. A second group was sacrificed 42 days postinjury for histological evaluation to measure cartilage degeneration and cartilage repair.Results: Seven days postinjury, there was a 45% reduction in chondrocyte PCD in the caspase inhibitor treated knees as compared to controls (P = 0.01). Forty-two days postinjury, treated knees were found to have 17.9% greater chondrocyte survival (P < 0.01) and 7.6% greater articular cartilage thickness (P = 0.01).Conclusions: Intra-articular administration of the caspase inhibitor Z-VAD-fmk effectively blocks chondrocyte PCD following experimental osteochondral injury in this model. Inhibition of chondrocyte PCD rescues chondrocytes that would otherwise die, limiting subsequent cartilage loss. To our knowledge, this study is the first to demonstrate that short-term inhibition of chondrocyte PCD leads to long-term preservation of cartilage in vivo. (c) 2006 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved.