Role of the tissue factor pathway in synovial inflammation.
OBJECTIVE
Clinical and experimental evidence suggests that extravascular fibrin deposition in arthritic joints is prominent and deleterious. The aim of this study was to investigate the contributions of tissue factor (TF) and its inhibitor, TF pathway inhibitor (TFPI), in arthritis.


METHODS
Synovial tissue specimens obtained from 10 patients with rheumatoid arthritis (RA) and 12 patients with osteoarthritis (OA) were scored histologically for inflammation and fibrin content. TF and TFPI levels were assayed at antigenic and functional levels. TF messenger RNA (mRNA) levels were determined using RNase protection assays. The effect of TF inhibition in murine antigen-induced arthritis (AIA) was assessed by administering systemically active site-blocked activated factor VIIa (FVIIai).


RESULTS
Functional TF activity was significantly increased in synovial membranes from RA patients compared with those from OA patients. In contrast, no difference in TF mRNA and TF antigenic levels was observed between these 2 groups. This discrepancy can be accounted for by TFPI, because we observed a negative correlation between TF activity and TFPI activity. There was a significant difference between the RA and OA groups in terms of synovial inflammation, with more inflammation observed in the RA group. Most importantly, TF activity was associated with fibrin (P = 0.024) and with histologic inflammation (P = 0.03) scores. In AIA, inhibition of TF-induced coagulation by FVIIai led, on day 9 of arthritis, to decreased synovial thickness and decreased articular cartilage damage, although only the latter difference between controls and treated mice reached significance (P < 0.04). Finally, in FVIIai-treated mice, there was a strong negative association between the prothrombin time and intraarticular fibrin deposition.


CONCLUSIONS
Our results show that TF expression in arthritic synovial tissue favors extravascular coagulation and may play a role in inflammation in RA. In this context, TF inhibitors may be of therapeutic value.
Busso
Nathalie
N
Laboratoire de Rhumatologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Nathalie.Busso@chuv.hospvd.ch
Morard
Carole
C
Salvi
Roberto
R
Péclat
Veronique
V
So
Alexander
A
D000368:Aged; D000818:Animals; D001169:Arthritis, Experimental / Q000517:prevention & control; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D003619:Dansyl Compounds / Q000627:therapeutic use; D004195:Disease Models, Animal; D015942:Factor VIIa / Q000627:therapeutic use; D005260:Female; D005337:Fibrin / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000378:metabolism* / Q000494:pharmacology; D006614:Hindlimb / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D011877:Radionuclide Imaging; D013585:Synovitis / Q000378:metabolism* / Q000473:pathology; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*
D003619:Dansyl Compounds; D005343:Fibrinolytic Agents; D008074:Lipoproteins; D012333:RNA, Messenger; C109749:dansyl-glutamyl-glycyl-arginyl-factor VIIa; C051928:lipoprotein-associated coagulation inhibitor; D005337:Fibrin; D013925:Thromboplastin; D015942:Factor VIIa