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Mechanisms Coupling Hemostatic Factors to Inflammatory Arthritis

Raghu, Harini

Abstract Details

2014, PhD, University of Cincinnati, Medicine: Immunology.
Rheumatoid Arthritis (RA) is a chronic, inflammatory disease of the joints that affects approximately 1% of the adult population worldwide. Characterized by persistent synovitis, edema, pannus, bone erosion and cartilage degradation, RA can result in irreversible functional impairment of the affected joint if left uncontrolled. Coagulation system activity is a prominent feature of RA, and specific links between the coagulation and inflammatory systems play a fundamental role in disease progression. The synovial fluid of RA patients contains reduced levels of coagulation factors in conjunction with corresponding increases in levels of thrombin-antithrombin complexes and fibrin degradation products, indicative of ongoing coagulation system activity. The overarching hypothesis of this thesis is that specific hemostatic factors (e.g., thrombin, factor XIII, plasminogen) of diverse functions are important, context-dependent determinants of inflammatory arthritis that make unique mechanistic contributions to arthritis pathogenesis. This hypothesis was tested using a combination of established murine models of inflammatory arthritis (e.g., CIA, TNF-transgenic mice), novel genetic tools and innovative pharmacological methods. Hemostatic factors of diverse biochemical and biological functions (i.e., the transglutaminase, fXIII and the serine protease zymogen plasminogen) were demonstrated to serve as powerful modifiers of inflammatory arthritis in mice that make functional contributions at various stages of the disease process through distinct mechanisms. First, the transglutaminase, factor XIII (fXIII), was shown to drive arthritis pathogenesis by promoting local inflammatory and tissue degradation. Using genetic or pharmacologic approaches, eliminating fXIII activity was demonstrated to limit arthritis severity and protect from cartilage/bone destruction in part through mechanisms linked to reduced RANKL-mediated osteoclastogenesis. Additionally, the role of the plasminogen-fibrinogen axis in the pathogenesis of TNF-driven inflammatory arthritis was explored using human TNFa transgenic Tg197 mice that develop spontaneous polyarthritis in the absence of any exogenous manipulation. These studies demonstrate that plasminogen is a key molecular determinant of inflammatory joint disease capable of simultaneously driving or ameliorating arthritis pathogenesis in distinct anatomical locations of the same subject. Plasminogen can either drive or ameliorate arthritis within the same animal as a function of anatomical location of the joint, the availability of fibrin(ogen), and the activation status of matrix metalloproteinase (MMP)-9. In conclusion, the work presented in this dissertation demonstrates that fibrin stabilization and fibrin dissolution are integral to the arthritic process and make unique mechanistic contributions to arthritis pathogenesis. This work strongly suggests that immunological as well as hematological factors determine the precise incidence and modulate the outcome of arthritis and suggests that targeting of hemostatic factors may be of therapeutic benefit for the treatment of inflammatory arthritides such as RA.
Matthew Flick, Ph.D. (Committee Chair)
Kasper Hoebe, Ph.D. (Committee Member)
Simon Hogan, Ph.D. (Committee Member)
William Ridgway, Ph.D. (Committee Member)
Susan Waltz, Ph.D. (Committee Member)
156 p.

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Citations

  • Raghu, H. (2014). Mechanisms Coupling Hemostatic Factors to Inflammatory Arthritis [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406900762

    APA Style (7th edition)

  • Raghu, Harini. Mechanisms Coupling Hemostatic Factors to Inflammatory Arthritis. 2014. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406900762.

    MLA Style (8th edition)

  • Raghu, Harini. "Mechanisms Coupling Hemostatic Factors to Inflammatory Arthritis." Doctoral dissertation, University of Cincinnati, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406900762

    Chicago Manual of Style (17th edition)