STUDIES OF THROMBIN-INDUCED PROTEOGLYCAN RELEASE IN THE DEGRADATION OF HUMAN AND BOVINE CARTILAGE

Because fibrin is commonly observed within arthritic joints, studies m ere undertaken to determine whether purified coagulation and fibrinoly tic proteases degrade cartilage in vitro and to seek evidence for the activation of coagulation in arthritic joints through measurements of the levels of inhibitor-enzmye complexes and several other proteins as sociated with coagulation and fibrinolysis. The concentrations of 13 p lasma proteins and complexes of thrombin and Factor Xa with antithromb in III were measured in synovial fluids recovered at the time of knee replacement surgery. All zymogens necessary to constitute the coagulat ion 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 disea sed cartilage only, and urokinase, tissue plasminogen activator, and a ctivated protein C were without effect at the levels used. At saturati ng levels of thrombin (greater than or equal to 2.0 mu M) 80% of the p roteoglycan content of normal cartilage was released within 24 h. Thro mbin, which is cationic, reversibly binds cartilage with K-d = 7.0 +/- 1.0 mu M and B-max = 820 +/- 70 ng/mg of human cartilage. Levels of t hrombin-antithrombin III complexes in synovial fluids and arthritis we re 4-fold higher in osteo(OA) and 43-fold higher in rheumatoid(RA) tha n in controls (0.98 nM). Factor Xa-antithrombin m complex levels were threefold lower in OA and fivefold higher in KA than in controls (0.24 nM). These elevated levels of enzyme-inhihitor complexes imply a hist ory of activation of coagulation within the joint, especially in IU. S ince thrombin degrades cartilage in vitro and had been generated in vi vo, as inferred by the existence of thrombin-antithrombin III complexe s, intraarticular activation of coagulation may both contribute to the pathology of arthritis and comprise a target for therapy and diagnosi s.