Aging and IGF-I in Cartilage

软骨中的衰老和 IGF-I

• 批准号: 7645773
• 负责人: RICHARD F LOESER
• 金额: $ 23.34万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7645773
• 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：骨关节炎（OA）发展的最重要的危险因素是年龄，但对OA易感性有助于衰老的机制知之甚少。 OA的一个关键特征是由于软骨细胞合成代谢和分解代谢活性失衡而导致关节软骨的进行性破坏和丧失。该项目的长期目标是确定衰老导致这种不平衡的机制。维持关节软骨的完整性需要软骨细胞对生长因子，细胞因子和细胞外基质产生的细胞信号的正确策划响应。该项目着重于导致软骨细胞对关键软骨生长因子IGF-I的软骨细胞反应下降的特定细胞和分子机制。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软骨细胞对IGF-I的反应中起关键作用，此外，可能会改变细胞信号传导途径的活性，从而导致合成代谢和分解代谢活性的失衡以及降低细胞存活。还发现软骨细胞表达愤怒（晚期糖基化最终产物的受体）。众所周知，愤怒信号传导会增加ROS的产生并激活NF B，从而启动促炎状态。已经发现，与年龄相关的氧化应激增加是导致许多组织衰老过程的关键因素，但是其在软骨衰老中的作用很少受到关注。因此，在该项目的延续中要检验的总体假设是，与年龄相关的软骨细胞对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失调细胞信号传导，导致的氧化应激和导致的“炎症”状态。具体目的是：1）测量从不同年龄的供体分离的人类关节软骨细胞的反应，当调节细胞氧化还原状态时，从不同年龄的供体分离到IGF-I； 2）确定调节软骨细胞对IGF-I的反应的氧化还原敏感细胞信号传导机制； 3）确定受体对晚期糖基化终产（RAGE）对软骨细胞氧化还原信号传导和IGF-I反应抑制的贡献。该项目的结果应继续提供需要建立基本的细胞和分子机制所需的新信息，这些信息将衰老与人类OA的发展联系起来。