The long-term goal of this research program is to understand the role of key hemostatic factors in inflammatory joint disease. The widespread deposition of fibrin (ogen) and fibrin degradation products within joints is one of the most conspicuous features of rheumatoid arthritis. Given that fibrin (ogen), plasmin(ogen), fibrin degradation products (FDPs), and their cell surface receptors have been shown to be important in both the inflammatory response and tissue remodeling/repair, hemostasis-related proteins are prime candidates to be critical determinants of inflammatory joint disease.
The aims of this project center on the following specific hypotheses: 1) fibrin (ogen) and plasmin-mediated proteolysis are important in the inflammatory processes leading to the synovial remodeling, pannus formation, neovascularization, cartilage destruction and bone erosion; 2) the mechanism by which fibrinogen contributes to the inopportune inflammatory and synovial cell activity leading progressive joint degeneration is coupled to: i) the local formation of provisional fibrin matrices, and ii) the local cellular engagement of fibrin(ogen) through specific integrin receptors; and 3) thrombin, the enzyme that proteolytically converts fibrinogen to fibrin, contributes to inflammatory joint disease through both fibrinogen-dependent and fibrinogen-independent mechanisms. These hypotheses will be tested by exploring the impact of genetic deficits and functional disorders in fibrinogen, plasminogen, and plasminogen activators on cytokine-driven and adaptive immunity-driven arthritis induced by either TNF-alpha transgene expression (Aim 1A) or immunization with type II collagen (Aim 1B). The specific importance of fibrinogen engagement of leukocyte and platelet integrin receptors in arthritis will be defined by comparative studies of arthritis in mice expressing mutant forms of fibrinogen lacking either the alpha-M-Beta-2 or alpha-IIb-beta-3 integrin binding motifs (Aim 2). Similarly, the importance of local thrombin-mediated conversion of fibrinogen to insoluble fibrin matrices in the pathogenesis of inflammatory joint disease will be defined in mice where thrombin activity is pharmacologically and/or genetically blocked (Aim 3). The proposed studies will provide a more detailed understanding of the role of hemostatic factors in the pathogenesis of arthritic disease with distinct etiologies, and could ultimately illuminate new therapeutic strategies for treating joint disease.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Hemostasis and Thrombosis Study Section (HT)
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Mancini, Marie
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Cincinnati Children's Hospital Medical Center
United States
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Vidal, Berta; Ardite, Esther; Suelves, Mònica et al. (2012) Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the ?M?2 leukocyte integrin receptor. Hum Mol Genet 21:1989-2004
Shanmukhappa, Kumar; Matte, Ursula; Degen, Jay L et al. (2009) Plasmin-mediated proteolysis is required for hepatocyte growth factor activation during liver repair. J Biol Chem 284:12917-23
Mullins, Eric S; Kombrinck, Keith W; Talmage, Kathryn E et al. (2009) Genetic elimination of prothrombin in adult mice is not compatible with survival and results in spontaneous hemorrhagic events in both heart and brain. Blood 113:696-704
Vidal, Berta; Serrano, Antonio L; Tjwa, Marc et al. (2008) Fibrinogen drives dystrophic muscle fibrosis via a TGFbeta/alternative macrophage activation pathway. Genes Dev 22:1747-52
Souri, Masayoshi; Koseki-Kuno, Shiori; Takeda, Naoki et al. (2008) Male-specific cardiac pathologies in mice lacking either the A or B subunit of factor XIII. Thromb Haemost 99:401-8
Flick, Matthew J; LaJeunesse, Christine M; Talmage, Kathryn E et al. (2007) Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin alphaMbeta2 binding motif. J Clin Invest 117:3224-35
Thornton, Sherry (2006) Contribution of angiogenic genes to the complex genetic trait underlying Kawasaki disease. Arthritis Rheum 54:1361-5