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.
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