Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin αMβ2 binding motif
Matthew J. Flick, … , Sherry Thornton, Jay L. Degen
Matthew J. Flick, … , Sherry Thornton, Jay L. Degen
Published October 11, 2007
Citation Information: J Clin Invest. 2007;117(11):3224-3235. https://doi.org/10.1172/JCI30134.
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Research Article Inflammation

Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin αMβ2 binding motif

Abstract

Fibrin deposition within joints is a prominent feature of arthritis, but the precise contribution of fibrin(ogen) to inflammatory events that cause debilitating joint damage remains unknown. To determine the importance of fibrin(ogen) in arthritis, gene-targeted mice either deficient in fibrinogen (Fib–) or expressing mutant forms of fibrinogen, lacking the leukocyte receptor integrin αMβ2 binding motif (Fibγ390–396A) or the αIIbβ3 platelet integrin-binding motif (FibγΔ5), were challenged with collagen-induced arthritis (CIA). Fib– mice exhibited fewer affected joints and reduced disease severity relative to controls. Similarly, diminished arthritis was observed in Fibγ390–396A mice, which retain full clotting function. In contrast, arthritis in FibγΔ5 mice was indistinguishable from that of controls. Fibrin(ogen) was not essential for leukocyte trafficking to joints, but appeared to be involved in leukocyte activation events. Fib– and Fibγ390–396A mice with CIA displayed reduced local expression of TNF-α, IL-1β, and IL-6, which suggests that αMβ2-mediated leukocyte engagement of fibrin is mechanistically upstream of the production of proinflammatory mediators. Supporting this hypothesis, arthritic disease driven by exuberant TNF-α expression was not impeded by fibrinogen deficiency. Thus, fibrin(ogen) is an important, but context-dependent, determinant of arthritis, and one mechanism linking fibrin(ogen) to joint disease is coupled to αMβ2-mediated inflammatory processes.

Authors

Matthew J. Flick, Christine M. LaJeunesse, Kathryn E. Talmage, David P. Witte, Joseph S. Palumbo, Malinda D. Pinkerton, Sherry Thornton, Jay L. Degen

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Figure 2

Microscopic analysis of the metacarpophalangeal joints of Fib+ and Fib– mice immunized with CII.

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Microscopic analysis of the metacarpophalangeal joints of Fib+ and Fib– ...
All joints were sectioned in the plane of the fore paw. (A and B) Representative joint sections from unchallenged Fib+ and Fib– mice. (C–H) Representative joint sections from CII-immunized Fib+ and Fib– mice harvested at day 40 and stained with hematoxylin and eosin. CIA-challenged Fib+ mice generally exhibited severe joint pathology, with individuals occasionally displaying obliterated joint architecture (C) and granulation tissue invading into the underlying trabecular bone. The metacarpophalangeal joints from Fib+ mice often displayed significant cartilage and bone erosion (E, arrowheads) with robust inflammatory infiltrates and synovial hyperplasia (G, arrows). Asterisk in C denotes pannus tissue. Joints from CII-immunized Fib– mice typically displayed far less overall joint space damage with only mild synovial inflammation and hyperplasia (D and F, arrows). Many metacarpophalangeal joints from CIA-challenged Fib– mice were nearly free of microscopically apparent disease (H). (I–L) Immunohistochemical stain of fibrin(ogen) within joints of unchallenged and CII-immunized mice harvested 40 days after primary CII immunization. No fibrin deposition was observed within joints from unchallenged Fib+ mice (I). However, robust fibrin staining (brown, denoted by asterisk) was observed within inflamed and hyperplastic synovial tissue (J) and on articular surfaces (K, arrows) in Fib+ mice. As expected, no fibrin(ogen) was detectable within joint sections prepared from CII-immunized Fib– mice (L) regardless of the degree of joint damage. Scale bar: 100 μm.