Oxidative Stress and the Development of Osteoarthritis

氧化应激与骨关节炎的发展

• 批准号: 8437793
• 负责人: RICHARD F LOESER
• 金额: $ 39.46万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8437793
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Age; Aging; Antioxidants; Cartilage; Cell Death; Cell Survival; Cells; Chemicals; Chondrocytes; Chronic; Collagen; Cysteine; Degenerative polyarthritis; Development; Disease; Disease Progression; Elderly; Enzymes; Exhibits; Generations; Genes; Human; Joints; Label; Link; MAPK8 gene; MEKs; Measures; Mechanics; Medial meniscus structure; Meniscus structure of joint; Mitochondria; Mitogen-Activated Protein Kinases; Modification; Mus; Normal Cell; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathway interactions; Phosphorylation; Play; Predisposition; Process; Protein Biosynthesis; Proteins; Proteoglycan; Proteomics; Reactive Oxygen Species; Regulation; Relative (related person); Respiratory Chain; Role; Second Messenger Systems; Serine; Severities; Signal Pathway; Signal Transduction; Signaling Protein; Source; Stress Tests; Synovial Cell; Testing; Tissues; Transfection; Transgenic Mice; Work; aged; articular cartilage; base; catalase; cytokine; disability; in vivo; inhibitor/antagonist; mitochondrial dysfunction; novel strategies; overexpression; oxidation; p66(ShcA) protein; response; second messenger; tert-Butylhydroperoxide

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.

描述（由申请人提供）：本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中细胞信号传导的机制，确定氧化应激促进骨关节炎（OA）发病的机制。 当ROS的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，但负责的机制尚未确定。 线粒体是细胞内ROS的重要来源，我们的初步研究表明，过氧化氢酶的过表达，靶向转基因小鼠的线粒体，降低年龄相关的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，当线粒体与抗氧化能力不足相结合时，导致过度的蛋白质氧化，使细胞信号传导转向有利于分解代谢， 合成代谢信号和促进细胞死亡。 我们的研究将集中在ROS水平过高破坏IRS-1-PI-3激酶-Akt信号通路的机制。 Akt在整合合成代谢和分解代谢信号以及促进细胞存活中起着核心作用。我们已经发现，在OA软骨细胞和诱导表现出氧化应激的正常细胞中，Akt活化被抑制，这与基质合成减少和细胞死亡易感性增加有关。我们将努力实现以下具体目标：1）确定在氧化应激过程中抑制软骨细胞中IRS-1-PI-3激酶-Akt信号传导的机制，并测试过量的ROS氧化激活MAP激酶途径的特异性蛋白质的假设，所述MAP激酶途径通过抑制IRS-1-PI-3激酶信号传导来抑制Akt 1活化，和2）确定靶向线粒体的过氧化氢酶过表达对小鼠骨关节炎发展的影响，并检验过氧化氢酶过表达将降低OA严重程度的假设。将研究对发现在抑制Akt中重要的信号蛋白的影响。这项工作的发现将用于开发新的治疗方法，以更有针对性的方法取代非靶向的一般抗氧化剂方法，这些方法针对受氧化应激影响并导致OA的特定途径。 公共卫生关系：骨关节炎是老年人慢性残疾的最常见原因，但缺乏减缓疾病进展的治疗方法。该项目的结果将提供有关骨关节炎中关节组织破坏的基本机制的新信息。需要这些信息来发现减缓或阻止疾病进展的新靶点。