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 alphaMbeta2 binding motif (Fibgamma390-396A) or the alphaIIbbeta3 platelet
integrin-binding motif (FibgammaDelta5), 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 Fibgamma390-396A mice, which retain full clotting function. In contrast,
arthritis in FibgammaDelta5 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 Fibgamma390-396A mice with CIA displayed reduced local expression of
TNF-alpha, IL-1beta, and
IL-6, which suggests that alphaMbeta2-mediated leukocyte engagement of
fibrin is mechanistically upstream of the production of proinflammatory mediators. Supporting this hypothesis, arthritic disease driven by exuberant
TNF-alpha 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 alphaMbeta2-mediated inflammatory processes.