Thrombin in the synovial fluid of patients with rheumatoid arthritis mediates proliferation of synovial fibroblast-like cells by induction of platelet derived growth factor.
OBJECTIVE
To investigate the clotting and fibrinolytic activities in synovial fluid (SF) from patients with rheumatoid arthritis (RA) and to examine the role of thrombin in synovial hyperplasia.


METHODS
We measured the amounts of thrombin-antithrombin-III complex (TAT), antithrombin-III (AT-III), thrombin, plasminogen, alpha 2-plasmin inhibitor (alpha 2-PI), and plasmin-alpha 2-antiplasmin complex (PAP) in SF of 20 patients with RA and 16 patients with osteoarthritis (OA). The proliferative response of synovial fibroblast-like cells to thrombin was measured using [3H] thymidine incorporation. Expression of platelet derived growth factors (PDGF) in conditioned medium was analyzed using a Western blot method, and expression of the mRNA of PDGF and their receptors was analyzed by reverse transcription polymerase chain reaction.


RESULTS
The amounts of clotting factors (TAT, AT-III) and fibrinolytic factors (plasminogen, alpha 2-PI, and PAP) were significantly higher in the patients with RA than in patients with OA (p < 0.01). Moreover, SF thrombin concentrations of patients with RA correlated significantly with erythrocyte sedimentation rates (rs = 0.751, p < 0.01) and serum C-reactive protein concentrations (rs = 0.531, p < 0.05). Thrombin exhibits mitogenic activity toward synovial fibroblast-like cells in vitro, and this mitogenic activity is associated with an increase in the expression of mRNA of both PDGF-alpha receptor and PDGF-beta-receptor.


CONCLUSIONS
The high levels of thrombin activity in the SF of patients with RA and strong mitogenic activity of thrombin toward the synovial fibroblast-like cells suggest that thrombin plays an important role in the pathogenesis of RA.
Ohba
T
T
Department of Internal Medicine II, Fukushima Medical College, Japan.
Takase
Y
Y
Ohhara
M
M
Kasukawa
R
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology*; D000077214:Becaplermin; D001779:Blood Coagulation Factors / Q000378:metabolism; D001799:Blood Sedimentation; D002097:C-Reactive Protein / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D005342:Fibrinolysis; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D009994:Osmolar Concentration; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics; D013582:Synovial Fluid / Q000378:metabolism*; D013583:Synovial Membrane / Q000473:pathology*; D013917:Thrombin / Q000494:pharmacology / Q000502:physiology*
D001779:Blood Coagulation Factors; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; C075278:platelet-derived growth factor A; D000077214:Becaplermin; D002097:C-Reactive Protein; D017479:Receptors, Platelet-Derived Growth Factor; D013917:Thrombin