Aging and IGF-I in Cartilage

软骨中的衰老和 IGF-I

• 批准号: 7896945
• 负责人: RICHARD F LOESER
• 金额: $ 0.74万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-06 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7896945
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Advanced Glycosylation End Products; Affect; Age; Aging; Aging-Related Process; Antioxidants; Attention; Biological Models; Cartilage; Cell Survival; Cells; Chondrocytes; Chronic; Degenerative polyarthritis; Development; Equilibrium; Extracellular Matrix; Extracellular Signal Regulated Kinases; Fibroblast Growth Factor 2; Fibronectins; Growth Factor; Human; In Vitro; Inflammatory; Injury; Insulin-Like Growth Factor I; Lead; Ligands; Link; Maintenance; Measures; Mechanics; Mitogen-Activated Protein Kinases; Molecular; NF-kappa B; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Play; Predisposition; Production; Reaction; Reactive Oxygen Species; Regulation; Research Personnel; Resistance; Risk Factors; Role; Signal Pathway; Signal Transduction; Testing; Tissue Donors; Tissues; Work; age related; ankle joint; articular cartilage; base; cartilage growth factor; cytokine; in vivo; normal aging; novel; programs; receptor; receptor expression; response

The most important risk factor for the development of osteoarthritis (OA) is age but the mechanisms by which aging contributes to OA susceptibility are poorly understood. A key feature of OA is the progressive destruction and loss of articular cartilage resulting from an imbalance in chondrocyte anabolic and catabolic activity. The long-term objective of this project is to determine the mechanisms by which aging contributes to this imbalance. Maintenance of the integrity of articular cartilage requires a properly orchestrated response of the chondrocyte to cell signals generated by growth factors, cytokines, and the extracellular matrix. This project focuses on the specific cellular and molecular mechanisms responsible for an age-related decline in the chondrocyte response to a key cartilage growth factor, IGF-I. Recent studies provide novel evidence that age-related oxidative stress may play a key role in reducing the chondrocyte response to IGF-I and, furthermore, could alter the activity of cell signaling pathways resulting in an imbalance in anabolic and catabolic activity as well as reduced cell survival. It has also been found that chondrocytes express RAGE (receptor for advanced glycation end-products). RAGE signaling is known to increase ROS production and activate NF B, initiating a pro-inflammatory state. An age-related increase in oxidative stress has been found to be a key contributor to aging processes in a number of tissues but its role in cartilage aging has received little attention. Therefore, the overall hypothesis to be tested in the continuation of this project is that an age-related chondrocyte resistance to IGF-I stimulation is due to dysregulated cell signaling resulting from the chronic and accumulated effects of oxidative stress and a resultant "pro-inflammatory" state. The specific aims will be to: 1) Measure the response of human articular chondrocytes, isolated from donors of different ages, to IGF-I when the cellular redox status has been modulated; 2) Determine the redox sensitive cell signaling mechanisms which regulate the chondrocyte response to IGF-I; and 3) Determine the contribution of the receptor for advanced glycation end-products (RAGE) to chondrocyte redox signaling and inhibition of the IGF-I response. The results from this project should continue to provide new information needed to establish the basic cellular and molecular mechanisms which link aging to the development of OA in humans.

开发骨关节炎（OA）的最重要危险因素是年龄，但机制是 衰老有助于OA易感性的理解很少。 OA的关键特征是进步 由软骨细胞合成代谢和 分解代谢活性。该项目的长期目标是确定衰老的机制 导致这种不平衡。维持关节软骨的完整性需要正确 软骨细胞对生长因子，细胞因子和细胞信号的策划反应 细胞外基质。该项目侧重于负责的特定细胞和分子机制 对于年龄相关的软骨细胞对关键软骨生长因子IGF-I的反应下降。最近的 研究提供了新的证据，表明与年龄相关的氧化应激可能在减少的关键作用中起关键作用 软骨细胞对IGF-I的反应，此外，可能会改变导致的细胞信号通路的活性 在合成代谢活性和分解代谢活性以及细胞存活率降低的情况下。也发现了 软骨细胞表达愤怒（晚期糖基化终产的受体）。愤怒信号是 已知会增加ROS产生并激活NF B，从而启动促炎状态。与年龄有关的 发现氧化应激的增加是导致衰老过程的关键因素 组织，但其在软骨衰老中的作用很少受到关注。因此，总体假设为 在该项目的延续中测试的是，与年龄有关的软骨细胞抗IGF-I刺激的抗性 是由于氧化应激的慢性和积累作用引起的细胞信号失调引起的 以及由此产生的“促炎”状态。具体目的是：1）衡量人类的反应 关节软骨细胞，从不同年龄的供体分离到IGF-I，当细胞氧化还原状态具有 被调制； 2）确定调节的氧化还原敏感细胞信号传导机制 软骨细胞对IGF-I的反应； 3）确定受体对晚期糖化的贡献 终产（RAGE）对软骨细胞氧化还原信号传导和IGF-I反应的抑制作用。结果 该项目应继续提供建立基本蜂窝的新信息和 分子机制将老化与人类OA的发展联系起来。