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）：该项目的长期目的是确定氧化应激的机制，通过关注反应性氧（ROS）改变关节软骨和拟象中的细胞信号的机制，从而有助于骨关节炎（OA）的发病机理。 当ROS水平超过细胞的抗氧化能力时，氧化应激会产生。 迄今为止的研究表明，氧化应激可能有助于OA中发现的基本过程，包括相对于合成代谢活性和细胞死亡过多的分解代谢，但尚未定义造成的机制。 线粒体是细胞内ROS的重要来源，我们的初步研究表明，抗氧化酶催化酶的过表达靶向转基因小鼠的线粒体，可降低与年龄相关的OA的严重程度。 我们提出，在OA中，线粒体会产生ROS的病理水平，当与抗氧化能力不足相结合时，它会导致过量的蛋白质氧化，从而将细胞信号转移以有利于分解代谢而不是 合成代谢信号传导并促进细胞死亡。 我们的研究将重点放在过度水平的ROS破坏IRS-1-PI-3激酶-akt信号通路的机制上。 AKT在整合合成代谢和分解代谢的信号以及促进细胞存活方面起着核心作用。我们发现，在OA软骨细胞和诱导的正常细胞中，Akt激活受到抑制，这与基质合成的降低和对细胞死亡的敏感性增加有关。 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关于小鼠骨关节炎发展的线粒体，并检验了过氧化氢酶过表达的假设将降低OA的严重程度。将研究发现对抑制AKT很重要的信号蛋白的影响。这项工作发现的发现将用于开发新的疗法，这些疗法将以更多针对受氧化应激影响的特定途径的更具针对性的方法来代替不受限制的一般抗氧化剂方法，并为OA贡献。 公共卫生相关性：骨关节炎是老年人慢性残疾的最常见原因，但缺乏疾病进展的治疗方法。该项目的结果将提供有关与骨关节炎关节组织分解有关的基本机制的新信息。为了发现减慢或阻止疾病进展的新目标，需要此信息。