Integrin Function in Cartilage

描述（由申请人提供）：该项目的长期目标是确定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，并启动一系列旨在重塑ECM的事件，但在关节炎中导致进一步的基质破坏。本提案的重点是通过a5b1整合素产生的信号，该整合素调节分解代谢介质的产生，包括细胞因子和基质金属蛋白酶（MMPs）。在最初的资助期间，确定了必须激活的关键信号蛋白，以便纤维连接蛋白片段（FN-f）刺激a5b1整合素，从而增加MMP-13的产生。重要的是，活性氧（ROS）被发现是激活这一信号通路所必需的二级信使。竞争性更新的总体目标将是确定关节软骨细胞中a5b1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测试假设，即特定半胱氨酸残基氧化为亚磺酸是导致MMP-13产生的a5b1整合素信号传导所必需的。这一重要且最近发现的细胞信号传导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。具体目的如下：1)确定a5b1整合素刺激关节软骨细胞后PYK2激活的氧化还原敏感机制；2)确定PYK2下游a5b1介导的MMP-13表达所需的关键氧化还原敏感信号蛋白；3)确定细胞因子信号传导3抑制因子（SOCS-3）在软骨细胞a5b1整合素信号传导中的作用。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）过程的基本分子机制，这些过程负责产生破坏性酶，这些酶已被发现导致关节炎患者软骨组织的降解和丧失。这项工作的成功完成将为抑制关节炎软骨破坏和预防或减缓关节炎的发展提供新的靶点。

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.