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 5

Diminished knee joint cartilage degradation in Fib– mice with CIA relative to Fib+ mice with CIA.

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Diminished knee joint cartilage degradation in Fib– mice with CIA relati...
(A) Representative knee joint sections prepared from Fib+ and Fib– mice with CIA on day 40 of the protocol and stained with Masson’s trichrome. Note the absence of contiguous Alcian blue stain, and thus the absence of cartilage, along much of the articular surface of Fib+ mice, whereas the majority of the articular surface of Fib– mice stained positive for Alcian blue. Arrows denote the position of the articular surface. (B) Percent of knee joint articular surface cartilage remaining intact and smooth on the tibias of Fib+ (n = 12) and Fib– (n = 9) mice with CIA. The articular surface length staining positive for Alcian blue was measured by morphometric analysis and compared with the total length of the articular surface of the tibia. Results are shown as mean ± SEM percent of Alcian blue staining. P < 0.00001, Student’s t test.