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The past 10 years have witnessed an increased interest in the plasminogen activation system and its potential role(s) in rheumatoid arthritis (RA). Two types of plasminogen activators (PAs), urokinase (uPA) and tissue type PA (tPA), which are structurally, immunologically, and genetically distinct, have been identified in mammals. Both PAs are secreted as a single chain protein, which in the case of uPA is essentially inactive (pro-uPA). Pro-uPA is then converted by a single enzymatic cleavage into two chain active enzyme. uPA and tPA are highly specific serine proteases catalysing the conversion of plasminogen into plasmin.1 ,2 Plasminogen, present in plasma and extracellular fluids, can bind to fibrin and also to cell surface plasminogen receptors (PlnR), via its lysine binding sites. The activity of PAs is controlled by natural inhibitors (PAls), which include PAI-1, the main PAI in the circulation, and PAI-2. In addition, uPA activity is blocked by protease nexin 1 (PN-1). Another important step in the regulation of PA activity involves binding of tPA to fibrin, leading to increased catalytic activity of the enzyme, and binding of pro-uPA and uPA through a growth factor domain contained in their amino terminal region, to a specific, high affinity cell surface receptor, uPAR. Binding of uPA to uPAR increases the rate of plasminogen activation and greatly increases extracellular matrix degradation and cell invasion in vitro and in vivo. In addition, upon binding to uPAR, uPA shows effects that are independent of its proteolytic activity.
Non-inflammatory synovial membranes from normal subjects or osteoarthritis patients expressed predominantly tPA, at the activity and antigenic level, which was associated to blood vessels.3 ,4 In contrast, in RA synovial tissues, tPA expression was reduced, while uPA activity was increased. Its corresponding antigen and mRNA were also increased, and mainly associated to the synovial …