Intra-articular tissue factor/factor VII complex induces chronic arthritis

Objective: Fibrin accumulation in the joint cavity is a common feature of chronic arthritides, such as rheumatoid arthritis (RA). Complex formation between tissue factor (TF) and factor VII (FVII) is the initial step in such a fibrin formation. Methods: To assess the role of the TF/FVII complex in the pathogenesis of joint inflammation, 1) the levels of TF/FVII complex were measured in synovial fluid of RA patients; 2) the complex was injected to healthy mice intra-articularly. Results: Morphological analysis of the joints 4 days after TF/FVII injection revealed influx of CD4-Mac1⁺ mononuclear leukocytes into synovial tissue followed by cartilage and bone destruction. Inflammation induced by TF/FVII complex was more profound than that caused by each of the proteins separately, both with respect to frequency, severity and duration of arthritis. Interaction between macrophages and lymphocytes in sustaining joint inflammation was proved by the requirement of the combined lymphocyte/monocyte depletion to abolish TF/FVII induced arthritis. Induction of monocyte attracting chemokines (MIP-1 α and RANTES) was shown to be one of the potential mechanisms for TF/FVII complex triggered inflammatory cell influx, Interestingly, TF/FVII complexes were detected in synovial fluid of 20/40 patients with RA. Conclusions: Altogether these findings indicate that TF/FVII complexes, frequently found intra-articularly in joints of RA patients, may be an important component in both induction and progression of chronic destructive arthritis.