Effect of thrombin inhibition on synovial inflammation in antigen induced arthritis

Varisco, Pierre Alain; Péclat, V; Ness, Karen Van; Bischof-Delaloye, A.; So, Alexander; Busso, Nathalie

doi:10.1136/ard.59.10.781

Cited by 61 publications

(61 citation statements)

References 24 publications

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“…Thrombin is the central hemostatic protease that initiates fibrin polymerization and was previously implicated as a major participant in the pathogenesis of experimental inflammatory joint disease. The potent thrombin inhibitor hirudin was shown to reduce joint disease severity in the mouse models of antigen-induced arthritis (AIA) and collagen-induced arthritis (CIA) (15,16). These findings were also correlated with both reduced fibrin deposition within joints and reduced local proinflammatory cytokine levels.…”

Section: Introductionmentioning

confidence: 51%

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

Flick

LaJeunesse²,

Talmage³

et al. 2007

J. Clin. Invest.

155

148

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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 α M β 2 binding motif (Fibγ 390-396A ) or the α IIb β 3 platelet integrin-binding motif (Fibγ Δ5 ), 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 Fibγ 390-396A mice, which retain full clotting function. In contrast, arthritis in Fibγ Δ5 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 Fibγ 390-396A mice with CIA displayed reduced local expression of TNF-α, IL-1β, and IL-6, which suggests that α M β 2 -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 α M β 2 -mediated inflammatory processes.

show abstract

Section: Introductionmentioning

confidence: 51%

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

Flick

LaJeunesse²,

Talmage³

et al. 2007

J. Clin. Invest.

155

148

View full text Add to dashboard Cite

show abstract

“…Deimination of fibrin could hamper its cleavage by plasmin, arginyl residues being included in the cleavage sites of this enzyme. The subsequent defect in fibrinolysis could have a role in perpetuating inflammation because fibrin accumulation in the ST has been demonstrated to play a pathogenic role in various animal models of arthritis (52)(53)(54). As, in this work, we demonstrate the presence of deiminated fibrin in other rheumatic diseases associated with synovitis, a deiminationrelated defect in fibrinolysis could constitute a general phenomenon contributing to the maintenance of ST inflammation.…”

Section: Discussionmentioning

confidence: 76%

Fibrin Deimination in Synovial Tissue Is Not Specific for Rheumatoid Arthritis but Commonly Occurs during Synovitides

Chapuy‐Regaud

Sebbag

Baeten

et al. 2005

The Journal of Immunology

118

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Autoantibodies to deiminated (citrullinated) proteins are the most specific serological markers of rheumatoid arthritis (RA). Deimination is critical in generating the peptidic epitopes they recognize. In the synovial tissue (ST), deiminated forms of the α- and β-chains of fibrin are their major autoantigenic targets (anti-human fibrin(ogen) autoantibodies (AhFibA)). We investigated whether the presence of deiminated fibrin in the ST was specific for RA, because this could explain why AhFibA are RA specific. In 13 patients with RA and 19 patients with various other rheumatological disorders, knee ST biopsies were collected in macroscopically inflamed areas identified under arthroscopy. Synovitis was histopathologically confirmed in all of the biopsies. By immunoblotting, using antisera to fibrin, Abs to citrullyl residues, and AhFibA purified from RA sera, deiminated fibrin was evidenced in ST extracts from all of the patients. Moreover, variations in the degree of fibrin deimination were observed that were not related to the disease. Immunohistochemical analysis, using Abs to citrullyl residues and an antiserum to fibrin on adjacent serial sections of ST, confirmed the results because deiminated proteins colocalized with fibrin in RA as well as in control patients. Therefore, fibrin deimination in the ST is a general phenomenon associated to any synovitis, which does not necessarily induce a B autoimmune response with production of AhFibA.

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“…9). Furthermore, blockade of this cascade using the thrombin inhibitor hirudin or inhibition of tissue factor reduces the severity of murine arthritis (10)(11)(12). Fibrin accumulation in the joint, a characteristic of arthritis (especially RA), is a consequence of this cascade (9,13) and may be detrimental due to impaired nutrition for the synovium and cartilage, leading to hypoxia and acidosis.…”

Section: Coagulation Cascadementioning

confidence: 99%

Emerging roles of serine proteinases in tissue turnover in arthritis

Milner

Patel

Rowan

2008

Arthritis & Rheumatism

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Effect of thrombin inhibition on synovial inflammation in antigen induced arthritis

Abstract: Hirudin reduces joint inflammation associated with AIA by fibrin-dependent and independent mechanisms.

Cited by 61 publications

References 24 publications

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

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

Fibrin Deimination in Synovial Tissue Is Not Specific for Rheumatoid Arthritis but Commonly Occurs during Synovitides

Emerging roles of serine proteinases in tissue turnover in arthritis

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