Integrin Function in Cartilage

描述（由申请人提供）：本项目的长期目标是确定通过整合素受体产生的信号调节软骨细胞功能的机制。这些研究的一般总体假设是软骨细胞外基质（ECM）的变化，包括ECM蛋白片段的产生，被软骨细胞整合素识别，并启动旨在重塑ECM的级联事件，但在关节炎中导致进一步的基质破坏。该建议的重点是通过α 5 β 1整联蛋白产生的信号，该整联蛋白调节包括细胞因子和基质金属蛋白酶（MMP）在内的分解代谢介质的产生。在最初的资助期间，定义了关键信号蛋白，其必须被激活以使纤连蛋白片段（FN-f）刺激α 5 β 1整联蛋白，从而导致MMP-13产生增加。重要的是，活性氧（ROS）被发现是必要的第二信使这个信号通路是活跃的。竞争性更新的总体目标是确定关节软骨细胞中a5 b1整合素信号通路中关键氧化还原调节信号事件的机制。一个独特的方面将是检验特定半胱氨酸残基氧化为次磺酸是导致MMP-13产生的α 5 β 1整联蛋白信号传导所必需的假设。这一重要的和最近发现的细胞信号调节机制尚未在软骨细胞中报道或在整合素信号通路中阐明。将追求以下具体目标：1）确定关节软骨细胞中α 5 β 1整联蛋白刺激后PYK 2活化的氧化还原敏感机制; 2）确定α 5 β 1介导的MMP-13表达所需的PYK 2下游的关键氧化还原敏感信号传导蛋白;和3）确定细胞因子信号传导抑制因子3（SOCS-3）在软骨细胞α 5 β 1整联蛋白信号传导中的作用。公共卫生相关性：这些研究的结果将提供新的和重要的信息，以了解控制软骨细胞（软骨细胞）中负责产生破坏性酶的过程的基本分子机制，这些酶已被发现会导致关节炎患者软骨组织的退化和损失。这项工作的成功完成将为抑制关节炎中软骨破坏提供新的靶点，并预防或减缓关节炎的发展。

DESCRIPTION (provided by applicant): The long-term goal of this project is to determine the mechanisms by which signals generated through integrin receptors regulate chondrocyte function. The general overall hypothesis for these studies is that changes in the cartilage extracellular matrix (ECM), including production of ECM protein fragments, are recognized by chondrocyte integrins and initiate a cascade of events intended to remodel the ECM but which in arthritis result in further matrix destruction. The focus of this proposal is on signals generated through the a5b1 integrin which regulate production of catabolic mediators including cytokines and matrix metalloproteinases (MMPs). During the initial funding period, key signaling proteins were defined that must be activated in order for fibronectin fragment (FN-f) stimulation of the a5b1 integrin to result in increased MMP-13 production. Importantly, reactive oxygen species (ROS) were found to be necessary secondary messengers for this signaling pathway to be active. The overall goal of the competitive renewal will be to determine the mechanism of key redox regulated signaling events in the a5b1 integrin signaling pathway in articular chondrocytes. A unique aspect will be testing of the hypothesis that oxidation of specific cysteine residues to sulfenic acid is necessary for a5b1 integrin signaling that results in MMP-13 production. This important and recently discovered mechanism for regulation of cell signaling has not been reported in chondrocytes or elucidated in integrin signaling pathways. The following specific aims will be pursued: 1) Determine the redox sensitive mechanism of PYK2 activation after a5b1 integrin stimulation in articular chondrocytes; 2) Determine the key redox sensitive signaling proteins downstream from PYK2 which are required for a5b1-mediated MMP-13 expression; and 3) Determine the role of the suppressor of cytokine signaling 3 (SOCS-3) in chondrocyte a5b1 integrin signaling. Public health relevance: The results from these studies will provide new and significant information needed to understand the basic molecular mechanisms which control processes in cartilage cells (chondrocytes) that are responsible for production of destructive enzymes that have been found to cause degradation and loss of cartilage tissue in people with arthritis. The successful completion of this work should provide novel targets for inhibiting cartilage destruction in arthritis and prevent or slow the development of arthritis.