Studies of thrombin-induced proteoglycan release in the degradation of human and bovine cartilage.

Abstract

Because fibrin is commonly observed within arthritic joints, studies were undertaken to determine whether purified coagulation and fibrinolytic proteases degrade cartilage in vitro and to seek evidence for the activation of coagulation in arthritic joints through measurements of the levels of inhibitor-enzyme complexes and several other proteins associated with coagulation and fibrinolysis. The concentrations of 13 plasma proteins and complexes of thrombin and Factor Xa with antithrombin III were measured in synovial fluids recovered at the time of knee replacement surgery. All zymogens necessary to constitute the coagulation cascade were present. Thrombin and the combination of prothrombin plus prothrombinase induced proteoglycan release from both normal and arthritic cartilages. Factor Xa and plasmin induced release from diseased cartilage only, and urokinase, tissue plasminogen activator, and activated protein C were without effect at the levels used. At saturating levels of thrombin (-2.0 ,uM) 80% of the proteoglycan content of normal cartilage was released within 24 h. Thrombin, which is cationic, reversibly binds cartilage with Kd = 7.0±1.0 ,uM and B__ = 820±70 ng/mg of human cartilage. Levels of thrombin-antithrombin m complexes in synovial fluids and arthritis were 4-fold higher in osteo(OA) and 43-fold higher in rheumatoid(RA) than in controls (0.98 nM). Factor Xaantithrombin III complex levels were threefold lower in OA and fivefold higher in RA than in controls (0.24 nM). These elevated levels of enzyme-inhibitor complexes imply a history of activation of coagulation within the joint, especially in RA. Since thrombin degrades cartilage in vitro and had been generated in vivo, as inferred by the existence of thrombin-antithrombin m complexes, intraarticular activation of coagulation may both contribute to the pathology of arthritis and comprise a target for therapy and diagnosis. (J. Clin. Invest. 1994. 94:472-480.)

The p38 mitogen-activated protein kinase pathway plays a critical role in thrombin-induced endothelial chemokine production and leukocyte recruitment

“…44 Extravascular coagulation is present in the joints in which tissue factor, fibrinogen, and fibronectin have been consistently detected. 45 Furthermore, high concentrations of thrombin have been found in rheumatoid arthritis synovial fluids, and thrombin may play a role in cartilage degradation, 46 synovial cell proliferation, 47 and leukocyte recruitment through adhesion molecule expression and chemokine production. [8][9][10]14,15 SB203580 has been used in 2 murine models of collagen-or adjuvant-induced arthritis and shown to decrease the severity of local inflammation as well as bone resorption at doses of 30 to 60 mg/kg.…”

Intraarticular factor IX protein or gene replacement protects against development of hemophilic synovitis in the absence of circulating factor IX

“…TF/VIIa activity is implicated in generating the thrombin and fibrin deposition that complicates RA and also in stimulation of vascular smooth muscle cell migration, 46 for example, via TF/VIIa activation of Protease Activated Receptor (PAR) 2. 56 Thrombin in turn is implicated in synovial thickening 48 and proteolysis of cartilage, 57 and these processes are also central to hemophilic synovitis. To carry the example further, thrombin activates PAR 1, which can up-regulate both pro-and anti-inflammatory chemokines.…”

Activated Protein C Inhibits Proliferation and Tumor Necrosis Factor α-Stimulated Activation of p38, c-Jun NH2-Terminal Kinase (JNK) and Akt in Rheumatoid Synovial Fibroblasts

“…Considering that synovial fibroblast proliferation is a hallmark of the invasive pannus in the RA joint and APC is significantly elevated in human RA synovial fluid compared with normal or osteoarthritic (OA) synovial fluids (20,21), it is possible that APC may contribute to the damage in RA. No data are available on the effects of APC on RSF proliferation.…”