Rheumatoid arthritis (RA) is a chronic autoimmune arthritis, characterized by synovitis, pannus formation and periarticular erosions. The mechanisms underlying disease initiation and progression in RA remain poorly understood. Tyrosine kinases play a central role in the activation of signal transduction pathways and the cellular responses that mediate the pathogenesis of RA. Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor developed to treat Bcr-Abl expressing leukemias. We recently demonstrated that imatinib potently prevents and treats collagen-induced arthritis (CIA) in mice. We showed that micromolar concentrations of imatinib abrogated multiple signal transduction pathways implicated in RA pathogenesis, including mast cell c-Kit signaling and TNFalpha release, macrophage c-Fms activation and cytokine production, and fibroblast PDGFRbeta signaling and proliferation. This application is to further characterize the relative roles of these pathways in RA. Our overriding hypothesis is that one or more of these signal transduction pathways and its downstream cellular responses contribute to initiation and progression of autoimmune arthritis. To investigate this hypothesis, we will explore inhibition of PDGFR, c-Kit, c-Fms, and c-Abl by testing small molecule kinase inhibitors in the collagen-induced arthritis (CIA) model for RA. We will perform immunohistochemistry on joint tissue derived from mice with CIA and human RA patients to characterize the in situ expression, activation and cellular distribution of PDGFR, c-Kit, c-Fms and c-Abl. Finally, we will apply phospho-protein flow cytometry to characterize the activation states of kinases and signaling pathways in mast cells, fibroblast-like synoviocytes, synovial macrophage, and B cells derived from human RA and OA synovial tissue. Success of the proposed studies will advance our understanding of the mechanisms underlying the pathobiology of RA, and could lead to clinical trials of selective tyrosine kinase inhibitors in RA. Relevance to public health: Rheumatoid arthritis (RA) is a chronic autoimmune arthritis that affects 0.6% of the world population. Current therapies are only partially effective, and there is great need for more effective therapeutic approaches. Tyrosine kinase inhibition represents a promising new therapeutic approach.
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