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. ? ? ?
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