In orthopedic research, many studies have applied vitamin E as a protective antioxidant or used -butyl hydroperoxide to induce oxidative injury to chondrocytes. These studies often support the hypothesis that joint pathology causes oxidative stress and increased lipid peroxidation that might be prevented with lipid antioxidants to improve cell survival or function and joint health; however, lipid antioxidant supplementation was ineffective against osteoarthritis in clinical trials and animal data have been equivocal. Moreover, increased circulating vitamin E is associated with increased rates of osteoarthritis. This disconnect between benchtop and clinical results led us to hypothesize that oxidative stress-driven paradigms of chondrocyte redox function do not capture the metabolic and physiologic effects of lipid antioxidants and prooxidants on articular chondrocytes. We used and cartilage models to investigate the effect of lipid antioxidants on healthy, primary, articular chondrocytes and applied immuno-spin trapping techniques to provide a broad indicator of high levels of oxidative stress independent of specific reactive oxygen species. Key findings demonstrate lipid antioxidants were pro-mitochondrial while lipid prooxidants decreased mitochondrial measures. In the absence of injury, radical formation was increased by lipid antioxidants; however, in the presence of injury, radical formation was decreased. In unstressed conditions, this relationship between chondrocyte mitochondria and redox regulation was reproduced with overexpression of glutathione peroxidase 4. In mice aged 18 months or more, overexpression of glutathione peroxidase 4 significantly decreased the presence of pro-mitochondrial peroxisome proliferation activated receptor gamma and deranged the relationship between mitochondria and the redox environment. This complex interaction suggests strategies targeting articular cartilage may benefit from adopting more nuanced paradigms of articular chondrocyte redox metabolism.

中文翻译：

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线粒体和脂质过氧化之间的相互关系决定了软骨细胞的细胞内氧化还原环境


在骨科研究中，许多研究应用维生素E作为保护性抗氧化剂或使用丁基过氧化氢来诱导软骨细胞的氧化损伤。这些研究通常支持这样的假设：关节病理学会导致氧化应激和脂质过氧化增加，而脂质过氧化可以通过脂质抗氧化剂来预防，从而改善细胞存活或功能以及关节健康；然而，在临床试验中，脂质抗氧化剂补充剂对骨关节炎无效，而且动物数据也模棱两可。此外，循环维生素 E 的增加与骨关节炎发病率的增加有关。台式结果与临床结果之间的这种脱节使我们假设氧化应激驱动的软骨细胞氧化还原功能范例无法捕捉脂质抗氧化剂和促氧化剂对关节软骨细胞的代谢和生理影响。我们使用软骨模型来研究脂质抗氧化剂对健康的初级关节软骨细胞的影响，并应用免疫自旋捕获技术来提供独立于特定活性氧的高水平氧化应激的广泛指标。主要发现表明，脂质抗氧化剂是促线粒体的，而脂质促氧化剂会降低线粒体指标。在没有损伤的情况下，脂质抗氧化剂会增加自由基的形成。然而，在存在损伤的情况下，自由基形成减少。在无应激条件下，软骨细胞线粒体和氧化还原调节之间的这种关系通过谷胱甘肽过氧化物酶 4 的过度表达而重现。 在 18 个月或以上的小鼠中，谷胱甘肽过氧化物酶 4 的过度表达显着减少了前线粒体过氧化物酶体增殖激活受体 γ 的存在，并扰乱了线粒体与氧化还原环境之间的关系。这种复杂的相互作用表明，针对关节软骨的策略可能受益于采用更细致的关节软骨细胞氧化还原代谢范例。