Mitochondrial Dysfunction in Osteoarthritis Is Associated With Down-Regulation of Superoxide Dismutase 2
Mitochondrial Dysfunction in Osteoarthritis Is Associated With Down-Regulation of Superoxide Dismutase 2
复制标题
DOI：
10.1002/art.37782
复制
发表时间：
2013-02-01
影响因子：
--
通讯作者：
Young, David A.
中科院分区：
文献类型：
--
作者：
Gavriilidis, Christos;Miwa, Satomi;Young, David A.
Objective.超氧化物歧化酶2（SOD 2）在骨关节炎（OA）中下调。本研究旨在探讨这种下调在氧化损伤和线粒体功能障碍背景下的功能影响。通过硫代巴比妥酸反应物质测定法测定丙二醛水平，评估OA患者和无病变对照股骨颈骨折患者关节软骨中的脂质过氧化作用。长距离聚合酶链反应扩增和线粒体DNA（mtDNA）链断裂试验被用来调查存在体细胞大规模的线粒体DNA重排在软骨。微尺度氧图用于探索OA和对照软骨细胞之间线粒体呼吸活性的可能变化。RNA干扰用于确定SOD 2耗竭对脂质过氧化、线粒体DNA损伤和线粒体呼吸的影响。OA软骨有更高水平的脂质过氧化反应相比，控制软骨，脂质过氧化反应也同样升高SOD2耗尽的软骨细胞。SOD2耗竭导致软骨细胞中mtDNA链断裂显著增加，但OA和对照软骨细胞之间的链断裂水平无显著差异。此外，只有非常低的水平的体细胞，大规模的线粒体DNA重排被确定在OA软骨。OA软骨细胞显示较少的备用呼吸能力（SRC）和较高的质子泄漏相比，对照软骨细胞。SOD2去除的软骨细胞也显示出更少的SRC和更高的质子漏。这是第一项研究，以分析在人类关节软骨细胞的氧化和线粒体功能的变化方面的SOD 2耗竭的影响。研究结果表明，软骨细胞中的SOD2耗竭导致氧化损伤和线粒体功能障碍，表明SOD2下调是OA发病机制的潜在贡献者。
Objective. Superoxide dismutase 2 (SOD2) is down-regulated in osteoarthritis (OA). This study was undertaken to investigate the functional effects of this down-regulation in the context of oxidative damage and mitochondrial dysfunction.Methods. Lipid peroxidation in articular cartilage from OA patients and from lesion-free control subjects with femoral neck fracture was assessed by measuring malondialdehyde levels using the thiobarbituric acid reactive substances assay. Long-range polymerase chain reaction amplification and a mitochondrial DNA (mtDNA) strand break assay were used to investigate the presence of somatic large-scale mtDNA rearrangements in cartilage. Microscale oxygraphy was used to explore possible changes in mitochondrial respiratory activity between OA and control chondrocytes. RNA interference was used to determine the effects of SOD2 depletion on lipid peroxidation, mtDNA damage, and mitochondrial respiration.Results. OA cartilage had higher levels of lipid peroxidation compared to control cartilage, and lipid peroxidation was similarly elevated in SOD2-depleted chondrocytes. SOD2 depletion led to a significant increase in mtDNA strand breaks in chondrocytes, but there was no notable difference in the level of strand breaks between OA and control chondrocytes. Furthermore, only very low levels of somatic, large-scale mtDNA rearrangements were identified in OA cartilage. OA chondrocytes showed less spare respiratory capacity (SRC) and higher proton leak compared to control chondrocytes. SOD2-depleted chondrocytes also showed less SRC and higher proton leak.Conclusion. This is the first study to analyze the effects of SOD2 depletion in human articular chondrocytes in terms of changes to oxidation and mitochondrial function. The findings indicate that SOD2 depletion in chondrocytes leads to oxidative damage and mitochondrial dysfunction, suggesting that SOD2 down-regulation is a potential contributor to the pathogenesis of OA.