Pharmacological Influence on the Biosynthesis and Activity of Plasmin, Plasminogen Activators and Their Inhibitor Pai-1

INTRODUCTION Production and activation of proteases, such as matrix metalloproteinases (MMPs), the recently identified aggrecanases (ADAMTS4 and ADAMTS11), and the plasminogen activator (PA)/plasmin system, are involved in the cartilage breakdown process during chronic inflammatory arthritides and osteoarthritis. The PAs are serine proteases, which catalyse the activation of plasminogen to plasmin. Two isoforms of PA exist: tissue-type PA (tPA) and urokinase-type PA (uPA). MMPs are synthesized and released from chondrocytes as inactive proenzymes, which are activated by limited proteolytic cleavage. Plasmin is a possible candidate involved in the activation process of these enzymes. Plasmin further contributes to cartilage matrix degradation by its direct proteolytic activity on extracellular macromolecules, such as proteoglycans. The PA activity is controlled by 2 distinct plasminogen activator inhibitors (PAIs), PAI-1 and PAI-2. Since one therapeutical approach in blocking the proteolytic destruction of articular cartilage can be the inhibition of enzymes responsible for the activation of MMPs, our presented study focus on the ability of drugs, used in the treatment of arthritic disorders, to inhibit the biosynthesis and/or activity of PAs and plasmin. As net proteolytic activity depends also on the amount of specific inhibitors, such as PAI-1, we also investigated the effects of these drugs on the biosynthesis of this inhibitor.