STUDIES OF THROMBIN-INDUCED PROTEOGLYCAN RELEASE IN THE DEGRADATION OF HUMAN AND BOVINE CARTILAGE
STUDIES OF THROMBIN-INDUCED PROTEOGLYCAN RELEASE IN THE DEGRADATION OF HUMAN AND BOVINE CARTILAGE
复制标题
DOI：
10.1172/jci117358
复制
发表时间：
1994-08-01
影响因子：
15.9
通讯作者：
NESHEIM, M
中科院分区：
文献类型：
--
作者：
FURMANIAKKAZMIERCZAK, E;COOKE, TDV;NESHEIM, M
由于纤维蛋白在关节炎关节中普遍存在，因此研究仅用于确定纯化的凝血和纤溶蛋白酶是否在体外降解软骨，并通过测量与凝血和纤溶相关的抑制剂-酶复合物和其他几种蛋白质的水平来寻找关节炎关节中凝血激活的证据。测定膝关节置换术后恢复的滑液中13种血浆蛋白及凝血酶、Xa因子与抗凝血酶III复合物的浓度。形成凝血级联所需的所有酵素都存在。凝血酶和凝血酶原加凝血酶原联合诱导正常软骨和关节炎软骨释放蛋白多糖。仅Xa因子和纤溶酶诱导病变软骨释放，尿激酶、组织纤溶酶原激活剂和活化蛋白C在使用的水平上没有影响。当凝血酶达到饱和水平（大于或等于2.0 μ M）时，正常软骨中80%的蛋白多糖含量在24小时内被释放。凝血酶是一种阳离子，可与人软骨的K-d = 7.0 +/- 1.0 μ M和B-max = 820 +/- 70 ng/mg可逆结合。滑膜液和关节炎中的凝血酶-抗凝血酶III复合物水平在骨性关节炎（OA）中比对照组高4倍，在类风湿关节炎（RA）中比对照组高43倍（0.98 nM）。与对照组相比，OA组xa -抗凝血酶m复合物水平低3倍，KA组高5倍（0.24 nM）。这些酶抑制剂复合物水平的升高暗示了关节内凝血活化的历史，特别是在IU中。由于凝血酶在体外降解软骨，并在体内产生，正如凝血酶-抗凝血酶III复合物的存在所推断的那样，关节内凝血激活可能既有助于关节炎的病理，也包括治疗和诊断的靶点。
Because fibrin is commonly observed within arthritic joints, studies mere 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-enzmye 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 (greater than or equal to 2.0 mu M) 80% of the proteoglycan content of normal cartilage was released within 24 h. Thrombin, 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 thrombin-antithrombin III 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 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 history of activation of coagulation within the joint, especially in IU. Since thrombin degrades cartilage in vitro and had been generated in vivo, as inferred by the existence of thrombin-antithrombin III complexes, intraarticular activation of coagulation may both contribute to the pathology of arthritis and comprise a target for therapy and diagnosis.