Oxidative Stress Promotes Peroxiredoxin Hyperoxidation and Attenuates Pro-survival Signaling in Aging Chondrocytes
Oxidative Stress Promotes Peroxiredoxin Hyperoxidation and Attenuates Pro-survival Signaling in Aging Chondrocytes
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DOI：
10.1074/jbc.m115.693523
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发表时间：
2016-03-25
影响因子：
4.8
通讯作者：
Loeser, Richard F.
中科院分区：
文献类型：
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作者：
Collins, John A.;Wood, Scott T.;Loeser, Richard F.
氧化应激介导的氧化还原敏感蛋白的翻译后修饰被认为是与年龄相关的细胞功能障碍和疾病进展的关键机制。过氧化物还毒素（PRX）是关键的细胞内抗氧化剂，也调节氧化还原信号事件。年龄相关性骨关节炎是一种常见的关节炎，与线粒体功能障碍和氧化应激有关。本研究的目的是确定衰老和氧化应激对软骨细胞胞内信号传导的影响，特别关注胞质PRX2和线粒体PRX3的氧化。以美那酮为模型诱导细胞氧化应激。与从年轻人身上分离的软骨细胞相比，在氧化应激条件下，老年人的软骨细胞表现出更高水平的PRX1-3超氧化。过氧化物还蛋白高氧化与促生存Akt信号的抑制和促死亡p38信号的刺激有关。在培养的人软骨细胞中，通过腺病毒表达靶向线粒体过氧化氢酶（MCAT）和MCAT转基因小鼠的软骨外植体可以阻止这些变化。老年人软骨切片和骨关节炎软骨原位观察到过氧还蛋白高氧化。MCAT转基因小鼠表现出较少的年龄相关性骨关节炎。这些发现表明，与年龄相关的氧化应激可以破坏正常的生理信号并导致骨关节炎，并提示过氧还蛋白高氧化是一种潜在的机制。
Oxidative stress-mediated post-translational modifications of redox-sensitive proteins are postulated as a key mechanism underlying age-related cellular dysfunction and disease progression. Peroxiredoxins (PRX) are critical intracellular antioxidants that also regulate redox signaling events. Age-related osteoarthritis is a common form of arthritis that has been associated with mitochondrial dysfunction and oxidative stress. The objective of this study was to determine the effect of aging and oxidative stress on chondrocyte intracellular signaling, with a specific focus on oxidation of cytosolic PRX2 and mitochondrial PRX3. Menadione was used as a model to induce cellular oxidative stress. Compared with chondrocytes isolated from young adult humans, chondrocytes from older adults exhibited higher levels of PRX1-3 hyperoxidation basally and under conditions of oxidative stress. Peroxiredoxin hyperoxidation was associated with inhibition of pro-survival Akt signaling and stimulation of pro-death p38 signaling. These changes were prevented in cultured human chondrocytes by adenoviral expression of catalase targeted to the mitochondria (MCAT) and in cartilage explants from MCAT transgenic mice. Peroxiredoxin hyperoxidation was observed in situ in human cartilage sections from older adults and in osteoarthritic cartilage. MCAT transgenic mice exhibited less age-related osteoarthritis. These findings demonstrate that age-related oxidative stress can disrupt normal physiological signaling and contribute to osteoarthritis and suggest peroxiredoxin hyperoxidation as a potential mechanism.