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Biologically active thrombomodulin is synthesized by adherent synovial
fluid cells and is elevated in synovial fluid of patients with rheumatoid
arthritis
EM Conway and B Nowakowski
Department of Medicine, Toronto Hospital, University of Toronto, Ontario,
Canada.
Thrombomodulin (TM) is a transmembrane glycoprotein that interacts with
thrombin, thereby serving as a cofactor in the activation of protein C, a
major physiologically relevant natural anticoagulant. Although initially
described as a vascular endothelial cell receptor, TM has also been
reported to be synthesized by several cells, including megakaryocytes,
platelets, monocytes, neutrophils (PMN), mesothelial cells, and synovial
lining cells. A prominent feature of rheumatoid arthritis (RA) is
infiltration of PMN into the joint space. To determine whether TM might
play a role in the inflammatory process, we examined synovial fluid for the
presence of TM in 10 patients with RA and five patients with osteoarthritis
(OA). We determined that the mean synovial fluid and plasma TM levels in
the OA group were 23.5 ng/mL and 24.2 ng/mL, respectively, whereas those
with RA had a significantly elevated mean synovial fluid TM level of 136.2
ng/mL as compared with the plasma TM concentration of 43.9 ng/mL (P <
.05). Synovial fluid TM levels did not correlate with PMN counts (r =
.261). Purified TM from synovial fluid was identical in molecular weight to
plasma-derived TM and was biologically functional with respect to protein C
cofactor activity. Using direct immunofluorescence, we determined that
adherent cultured synovial fluid cells that are not monocytoid in origin
express surface and cytoplasmic TM, thereby providing an alternative source
of the protein. Biologic activity of the cell-surface TM was confirmed by
acceleration of thrombin-dependent protein C activation. Northern analysis
of RNA extracted from the cultured cells indicated that TM messenger RNA
was present, suggesting local synthesis. Our results indicate that in
RA-associated synovial effusions, biologically active TM is increased, the
source of which may be from plasma, PMN, and/or synovial lining cells. TM
may play a regulatory role either in fibrin deposition in the inflamed
joint and/or in the progression of the inflammatory process.
Volume 81,
Issue 3,
pp. 726-733,
02/01/1993
Copyright © 1993 by The American Society of Hematology
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