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）：该项目的长期目标是通过关注活性氧（ROS）改变关节软骨和半月板细胞信号传导的机制，确定氧化应激导致骨关节炎（OA）发病机制。 当 ROS 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，氧化应激可能导致骨关节炎的基本过程，包括相对于合成代谢活动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，针对转基因小鼠线粒体的抗氧化酶过氧化氢酶的过度表达，可以减轻与年龄相关的 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，当与抗氧化能力不足相结合时，会导致蛋白质过度氧化，从而使细胞信号转而有利于分解代谢。 合成代谢信号并促进细胞死亡。 我们的研究将重点关注过量 ROS 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传导以及促进细胞存活方面发挥着核心作用。我们发现，在 OA 软骨细胞和被诱导表现出氧化应激的正常细胞中，Akt 激活受到抑制，这与基质合成减少和细胞死亡敏感性增加有关。我们将追求以下具体目标：1) 确定氧化应激期间软骨细胞中 IRS-1-PI-3 激酶-Akt 信号传导抑制的机制，并测试以下假设：过量的 ROS 会氧化激活 MAP 激酶途径的特定蛋白，从而通过抑制 IRS-1-PI-3 激酶信号传导抑制 Akt1 激活；2) 确定过氧化氢酶靶向过度表达的影响 线粒体对小鼠骨关节炎发展的影响，并检验过氧化氢酶的过度表达将降低 OA 严重程度的假设。将研究对抑制 Akt 重要的信号蛋白的影响。这项工作的发现将用于开发新疗法，以针对受氧化应激影响并导致 OA 的特定途径的更有针对性的方法来取代无针对性的一般抗氧化方法。 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关节组织破坏相关基本机制的新信息。为了发现减缓或阻止疾病进展的新靶标，需要这些信息。