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Oxidative Stress and the Development of Osteoarthritis

氧化应激与骨关节炎的发展

基本信息

批准号：
10659765
负责人：
RICHARD F LOESER
金额：
$ 44.4万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659765
关键词：
Aging Alanine Amino Acids Antioxidants Biology Cell Aging Cell Death Cell model Cells Chondrocytes Chronic Cysteine Degenerative polyarthritis Development Disease Disease Progression Elderly Engineering Enzymes Event Exhibits Family Fibroblasts Funding Future Genetic Transcription Glutathione Disulfide Goals Human Hydrogen Peroxide Inflammatory Investigation JNK-activating protein kinase Joints Literature MAPK8 gene MAPK9 gene Maintenance Measures Mediator Mitochondria Modification Mus NADP Oxidases Oxidation-Reduction Oxidative Stress PRDX3 peroxidase Pathogenesis Pathologic Pathway interactions Phenotype Phosphorylation Physiological Production Proteins Proto-Oncogene Proteins c-akt Reactive Oxygen Species Reporter Role Severities Signal Pathway Signal Transduction Signaling Protein Sorting Sulfhydryl Compounds Supporting Cell System TXNIP gene Tissues Transgenic Mice Transgenic Organisms Work age related cell type comparison control cytokine disability genetic approach in vivo innovation joint function knock-down mouse model novel novel therapeutics overexpression oxidation oxidative damage p38 Mitogen Activated Protein Kinase peroxiredoxin phosphoproteomics senescence tool

项目摘要

Project Summary The long-term objective of this project is to determine the basic mechanisms by which oxidative stress conditions contribute to the pathogenesis of osteoarthritis (OA), with a focus on age-related OA. Oxidative stress occurs when the production of reactive oxygen species (ROS) overwhelms the cellular antioxidant capacity, resulting in disturbances in the control of redox signaling. Peroxiredoxins are a family of antioxidant proteins that control the local levels of H2O2 in the cell and serve to regulate redox signaling events. Work in this project during the current funding period, using human cells, innovative redox biology tools, and unique mouse models, has shown that oxidative stress disrupts homeostatic signaling in chondrocytes by oxidative inactivation of the peroxiredoxins to favor p38 signaling and activation of NFκB over JNK and AKT signaling. It was found that, unlike physiologic levels of H2O2 that activate JNK, pathologic levels inactivate JNK through oxidation of specific cysteine thiols. The loss of JNK signaling alters the function of joint tissues. Deletion of JNK in mice promoted cell senescence and increased the severity of age-related OA, while transgenic mice engineered to overexpress peroxiredoxin-3 in chondrocytes developed less severe age-related OA. A central mechanism by which cell senescence promotes age-related diseases is through the production of inflammatory cytokines and matrix degrading enzymes by senescent cells, referred to as the senescence-associated secretory phenotype (SASP). The overall hypothesis for this renewal is that oxidative stress contributes to the development of OA by activating signaling events in senescent joint tissue cells that promote and maintain the SASP. Aims are: 1) Determine the mechanism by which redox signaling under oxidative stress conditions promotes the development of the SASP. Hypothesis: Oxidative stress creates an imbalance in JNK and p38 activity, favoring p38, to promote the SASP. 2) Identify the role of the endogenous antioxidant systems in regulating the development of the SASP. Hypothesis: Inactivation of one or more of the peroxiredoxins, due to hyperoxidation or NADPH depletion, contributes to the altered redox signaling controlling the SASP. These studies will define a novel mechanism by which disturbed redox signaling, due to oxidative stress in joint tissues, promotes development of OA through the SASP. The results will support the future development of novel therapeutics for OA that control the SASP by targeting specific proteins within redox signaling pathways that promote and maintain the SASP. This “senomorphic” approach of altering the secretory phenotype of senescent cells will provide an important alternative to a “senolytic” strategy of targeted cell death.

项目概要该项目的长期目标是确定氧化的基本机制应激条件会导致骨关节炎 (OA) 的发病机制，尤其是与年龄相关的 OA。当活性氧 (ROS) 的产生超过了机体的代谢能力时，就会发生氧化应激。细胞抗氧化能力，导致氧化还原信号控制紊乱。过氧化还原蛋白是一个抗氧化蛋白家族，控制细胞中 H2O2 的局部水平并用于调节氧化还原信号事件。在当前资助期间参与该项目，使用人体细胞，创新的氧化还原生物学工具和独特的小鼠模型表明，氧化应激会破坏通过过氧化还原蛋白的氧化失活以支持 p38，从而在软骨细胞中实现稳态信号传导 NFκB 信号传导以及 JNK 和 AKT 信号传导的激活。研究发现，与生理学不同激活 JNK 的 H2O2 水平，病理水平通过特定的氧化作用使 JNK 失活半胱氨酸硫醇。 JNK 信号传导的丧失会改变关节组织的功能。小鼠中 JNK 的缺失促进细胞衰老并增加与年龄相关的 OA 的严重程度，而转基因小鼠经过改造，在软骨细胞中过度表达过氧化还原蛋白-3，导致与年龄相关的 OA 的严重程度减轻。一个细胞衰老促进与年龄相关的疾病的中心机制是通过衰老细胞产生炎症细胞因子和基质降解酶，称为作为衰老相关的分泌表型（SASP）。本次更新的总体假设氧化应激通过激活体内的信号事件促进 OA 的发展促进和维持 SASP 的衰老关节组织细胞。目标是： 1) 确定氧化应激条件下氧化还原信号促进的机制 SASP 的开发。假设：氧化应激导致 JNK 和 p38 失衡活动，有利于 p38，以促进 SASP。 2) 确定内源性抗氧化剂的作用规范 SASP 发展的制度。假设：一种或多种失活由于过度氧化或 NADPH 耗尽，过氧化还原蛋白会导致氧化还原的改变控制 SASP 的信令。这些研究将定义一种新的机制，通过该机制由于关节组织中的氧化应激，氧化还原信号通过以下途径促进 OA 的发展： SASP。研究结果将支持未来开发控制 OA 的新疗法 SASP 通过靶向氧化还原信号通路中的特定蛋白质来促进和维持 SASP。这种改变衰老细胞分泌表型的“衰老”方法将为靶向细胞死亡的“senolytic”策略提供了一种重要的替代方案。