The urokinase-type plasminogen activator system and inflammatory joint diseases

Much evidence indicates that the urokinase plasminogen activator (u-PA), the urokinase receptor (u-PAR) and the serpin inhibitors are critical in cell invasion processes. The balance between u-PAR-bound u-PA and inhibitors modulate a pericellular proteolytic activity able to give "stop and go" signals to invading cells. The plasminogen activation system operates both directly and in concert with the matrix-metalloproteinase system. Direct interactions of u-PAR with vitronectin and integrins further regulate cell invasion. Another line of evidence suggests that u-PA-u-PAR interaction elicits chemotaxis, chemoinvasion and cell multiplication, events that do not require plasmin generation and therefore are referred to as "plasminogen-independent". Following the description of the main molecular and functional characteristics of the cell-surface-associated plasminogen activation system, we discuss here the observations indicating a role of this system in many aspects of the rheumatic diseases, ranging from the infiltration of inflammatory cells into the affected joint, infiltration of synovial cells into the underlying cartilage, and remodeling of the cartilage itself. Evidence of the intraarticular cytokine- and growth factor-dependent regulation of the components of the plasminogen activation system are presented in terms of the paracrine and autocrine regulation of receptor-associated fibrinolysis. The roles of plasminogen-dependent and plasminogen-independent u-PAR-associated events in various phases of joint inflammation are also discussed. A knowledge of these processes is required for the therapeutic utilization of antagonists of the u-PA/u-PAR system able to control the activity of proliferating and invading cells in inflammatory joint diseases.