Mitochondrial DNA damage is involved in apoptosis caused by pro-inflammatory cytokines in human OA chondrocytes
Mitochondrial DNA damage is involved in apoptosis caused by pro-inflammatory cytokines in human OA chondrocytes
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DOI：
10.1016/j.joca.2009.09.008
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发表时间：
2010-03-01
影响因子：
7
通讯作者：
Grishko, V.
中科院分区：
文献类型：
--
作者：
Kim, J.;Xu, M.;Grishko, V.
目的：促炎细胞因子在骨关节炎（OA）进展过程中软骨破坏中起关键作用。此外，这些细胞因子能够在软骨细胞内产生活性氧和活性氮。线粒体是氧化损伤的主要目标，也是衰老和退行性过程的重要参与者。本研究的目的是研究这些细胞因子是否会改变正常和骨关节炎患者软骨细胞的线粒体DNA完整性和线粒体功能。设计：将原代正常和骨关节炎的人软骨细胞培养物暴露于不同浓度的白细胞介素-1 β (IL-1 β)和肿瘤坏死因子- α (tnf - α)中不同时间。暴露后，对软骨细胞进行线粒体DNA损伤、ATP产生、线粒体转录变化和凋亡的评估。利用腺病毒载体将DNA修复酶hOGG1传递到线粒体。结果：促炎因子IL-1 β和tnf - α通过诱导线粒体DNA损伤，降低能量产生和线粒体转录，干扰人软骨细胞线粒体功能，与诱导细胞凋亡相关。NO的产生增加是细胞因子暴露后mtDNA损伤积累的关键因素。在促炎细胞因子暴露后，线粒体超氧化物的产生也增加。OA软骨细胞线粒体比正常软骨细胞线粒体更容易受到促炎细胞因子的损伤。线粒体靶向DNA修复酶hOGG1保护人软骨细胞免受mtDNA损伤，挽救了mtDNA的完整性，保持了ATP水平，重建了线粒体转录，并显著减少了IL-1 β和tnf - α暴露后的凋亡。结论：线粒体是促炎细胞因子毒性的重要靶点，维持线粒体DNA完整性是防止IL-1 β和tnf - α诱导软骨细胞凋亡的必要条件。(C) 2009国际骨关节炎研究学会。Elsevier Ltd.出版。版权所有。
Objective: Pro-inflammatory cytokines play a pivotal role in cartilage destruction during the progression of osteoarthritis (OA). Additionally, these cytokines are capable to generate reactive oxygen and nitrogen species within chondrocytes. Mitochondrion is a prime target of oxidative damage and an important player in aging and degenerative processes. The purpose of the present study was to investigate whether these cytokines will alter the mitochondrial DNA (mtDNA) integrity and mitochondrial function in both normal and osteoarthritic human chondrocytes.Design: Primary normal and osteoarthritic human chondrocyte cultures were exposed to various concentrations of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) for different time. Following exposure, chondrocytes were evaluated for mitochondrial DNA damage, ATP production, changes in mitochondrial transcription, and apoptosis. Adenoviral vectors were used to deliver DNA repair enzyme hOGG1 to mitochondria.Results: Pro-inflammatory cytokines IL-1 beta and TNF-alpha disturb mitochondrial function in human chondrocytes by inducing mitochondrial DNA damage, decreasing energy production and mitochondrial transcription, which correlated with the induction of apoptosis. Increased NO production was the key factor responsible for accumulation of mtDNA damage after cytokine exposure. Mitochondrial superoxide production was also enhanced following pro-inflammatory cytokine exposure. OA chondrocyte mitochondria were more susceptible to damage induced by pro-inflammatory cytokines then mitochondria from normal chondrocytes. Protection of human chondrocytes from mtDNA damage by the mitochondria-targeted DNA repair enzyme hOGG1 rescued mtDNA integrity, preserved ATP levels, reestablished mitochondrial transcription, and significantly diminished apoptosis following IL-1 beta and TNF-alpha exposure.Conclusion: Mitochondrion is an important target in pro-inflammatory cytokine toxicity, maintaining of mitochondrial DNA integrity is necessary to prevent chondrocytes from apoptosis induced by IL-1 beta and TNF-alpha. (C) 2009 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.