Oxidative Stress and the Development of Osteoarthritis

描述（由申请人提供）：该项目的长期目标是通过关注活性氧（ROS）改变关节软骨和半月板细胞信号的机制，确定氧化应激促进骨关节炎（OA）发病的机制。当活性氧水平超过细胞的抗氧化能力时，就会产生氧化应激。迄今为止的研究表明，氧化应激可以促进OA中发现的基本过程，包括相对于合成代谢活性的过度分解代谢和细胞死亡，但其机制尚未明确。线粒体是细胞内ROS的重要来源，我们的初步研究表明，在转基因小鼠中，靶向线粒体的抗氧化酶过氧化氢酶的过度表达可以降低年龄相关OA的严重程度。我们认为，在OA中，病理水平的ROS是由线粒体产生的，当线粒体与缺乏抗氧化能力相结合时，会导致过度的蛋白质氧化，从而使细胞信号转向有利于分解代谢的方向

DESCRIPTION (provided by applicant): The long-term objective of this project is to determine the mechanisms by which oxidative stress contributes to the pathogenesis of osteoarthritis (OA) by focusing on mechanisms by which reactive oxygen species (ROS) alter cell signaling in the articular cartilage and meniscus. Oxidative stress results when levels of ROS exceed the anti-oxidant capacity of cells. Studies to date suggest that oxidative stress can contribute to fundamental processes found in OA, including excessive catabolic relative to anabolic activity and cell death, but the mechanisms responsible have not been defined. Mitochondria are an important source of intracellular ROS and our preliminary studies demonstrate that overexpression of the anti-oxidant enzyme catalase, targeted to the mitochondria in transgenic mice, reduces the severity of age-associated OA. We propose that in OA, pathological levels of ROS are generated by the mitochondria which, when combined with a deficient anti-oxidant capacity, results in excessive protein oxidation that shifts cell signaling to favor catabolic over anabolic signaling and to promote cell death. Our studies will focus on mechanisms by which excessive levels of ROS disrupt the IRS-1-PI-3 kinase-Akt signaling pathway. Akt plays a central role in integrating anabolic and catabolic signaling as well as in promoting cell survival. We have found that in OA chondrocytes and in normal cells induced to exhibit oxidative stress, Akt activation is inhibited and this is associated with reduced matrix synthesis and increased susceptibility to cell death. We will pursue the following specific aims: 1) Determine the mechanism for inhibition of IRS-1-PI-3kinase-Akt signaling in chondrocytes during oxidative stress and test the hypothesis that excessive levels of ROS oxidize specific proteins that activate the MAP kinase pathway which inhibits Akt1 activation through inhibition of IRS-1-PI-3 kinase signaling and 2) Determine the effects of overexpression of catalase targeted to the mitochondria on the development of osteoarthritis in mice and test the hypothesis that overexpression of catalase will reduce OA severity. Effects on the signaling proteins discovered to be important in inhibiting Akt will be studied. The discoveries made by this work will be used to develop new therapies that would replace the untargeted general anti-oxidant approach with more a more targeted approach aimed at the specific pathways affected by oxidative stress and contributing to OA. PUBLIC HEALTH RELEVANCE: Osteoarthritis is the most common cause of chronic disability in older adults but treatments to slow the progression of the disease are lacking. The results from this project will provide new information about basic mechanisms relevant to joint tissue breakdown in osteoarthritis. This information is needed in order to discover new targets for slowing or stopping the progression of the disease.