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。提出的工作的重点是在功能的变化相关的软骨破坏的发展中看到的关节炎。整合素是一种粘附受体异二聚体，通过激活特定的细胞信号通路将信息从细胞外基质（ECM）传递到细胞。先前的研究表明，软骨细胞表达整合素家族的几个成员，作为软骨基质蛋白的受体。这项工作的重要意义在于，整合素调节细胞功能的许多机制是细胞类型特异性的，对软骨中的整合素功能知之甚少。破坏和退化的软骨ECM是一个中心特征在关节炎的发展。提出的研究的一般假设是，软骨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。具体来说，假设通过α 5beta1纤维连接蛋白（FN）受体响应纤维连接蛋白片段而产生的信号上调了金属蛋白酶（MMP）的产生和活性。初步数据表明，通过alpha5beta1启动的MAP激酶信号上调了MMP-13的产生。研究其细胞和分子机制有以下具体目的：(1)确定导致MMP-13表达增加的alpha5beta1所利用的信号通路；(2)确定细胞因子是否在整合素刺激的MMP-13表达和活性增加中起自分泌中介作用；(3)确定软骨细胞内整合素信号是否产生活性氧（ROS），并确定其在介导MMP-13产生和活性中的作用。在所有三个Aims中，MMP-13的表达结果将与MMP-1和MMP-3进行比较。这些研究将为进一步开发旨在抑制关节炎软骨基质破坏的疗法提供重要的新信息。

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 focus of the proposed work is on changes in function relevant to the development of the cartilage destruction seen in arthritis. Integrins are adhesion receptor heterodimers that transmit information from the extracellular matrix (ECM) to the cell through activation of specific cell signaling pathways. Previous studies have shown that chondrocytes express several members of the integrin family that serve as receptors for cartilage matrix proteins. Important to the significance of this work, many of the mechanisms by which integrins regulate cell function are cell-type-specific and little is known about integrin function in cartilage. Disruption and degradation of the cartilage ECM is a central feature in the development of arthritis. The general hypothesis for the proposed studies is that changes in the cartilage 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. Specifically, it is hypothesized that signals generated through the alpha5beta1 fibronectin (FN) receptor in response to fibronectin fragments upregulate metalloproteinase (MMP) production and activity. Preliminary data demonstrates that MAP kinase signals initiated through alpha5beta1 upregulate MMP-13 production. The cellular and molecular mechanisms responsible will be studied with the following Specific Aims: (1) to define the signaling pathways utilized by alpha5beta1 which result in increased MMP-13 expression; (2) to determine if cytokines serve as autocrine intermediates in the integrin-stimulated increase in MMP-13 expression and activity; (3) to determine if reactive oxygen species (ROS) are generated by integrin signals in chondrocytes and determine their role in mediating MMP-13 production and activity. In all three Aims, results of MMP-13 expression will be compared to MMP-1 and MMP-3. These studies will provide important new information needed to further develop therapies designed to inhibit cartilage matrix destruction in arthritis.