Aging and IGF-I in Cartilage

骨性关节炎发生的最重要的危险因素是年龄，但其发病机制是 究竟是哪种衰老导致了骨性关节炎的易感性，目前还知之甚少。办公自动化的一个关键特征是渐进性 软骨细胞合成代谢失衡所致的关节软骨破坏和丢失 分解代谢活动。该项目的长期目标是确定衰老的机制 导致了这种不平衡。保持关节软骨的完整性需要适当的 软骨细胞对生长因子、细胞因子和细胞因子产生的细胞信号的协调反应 细胞外基质。这个项目的重点是特定的细胞和分子机制。 对于软骨细胞对关键的软骨生长因子IGF-I的反应与年龄相关的下降。近期 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，进而可以改变导致的细胞信号通路的活性 导致合成代谢和分解代谢活性失衡，细胞存活率降低。它也被发现了 软骨细胞表达RAGE(晚期糖基化终末产物受体)。愤怒的信号是 已知可增加ROS的产生并激活核因子B，启动促炎状态。与年龄相关的 氧化应激的增加被发现是许多人衰老过程的关键因素 但其在软骨老化中的作用却鲜有人关注。因此，总体假设是 在这个项目的继续过程中测试的是与年龄相关的软骨细胞对IGF-I刺激的抵抗力 是由于氧化应激的慢性累积效应引起的细胞信号失控 以及由此产生的“促炎”状态。具体目标将是：1)测量人类的反应 从不同年龄的供者分离的关节软骨细胞，当细胞氧化还原状态为 2)确定对氧化还原敏感的细胞信号转导机制。 软骨细胞对IGF-I的反应；以及3)决定晚期糖基化受体的作用 最终产物(RAGE)到软骨细胞氧化还原信号和抑制IGF-I反应。结果来自于 该项目应继续提供所需的新信息，以建立基本的细胞和 衰老与人类骨性关节炎发生发展相关的分子机制。

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.