Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation

The molecular mechanisms predisposing to atherosclerotic aneurysm formation remain undefined(1-5). Nevertheless, rupture of aortic aneurysms is a major cause of death in Western societies, with few available treatments and poor long-term prognosis. Indirect evidence suggests that matrix metalloproteinases (MMPs) and plasminogen activators (PAs) are involved in its pathogenesis (1,6-12). MMPs are secreted as inactive zymogens (pro-MMPs), requiring activation in the extracellular compartment(11,13). Plasmin, generated from the zymogen plasminogen by tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA; refs 14,15), has been proposed as a possible activator in vitro, but evidence for such a role in vivo is lacking(16,17) . Analysis of atherosclerotic aorta in mice with a deficiency of apoliprotein E (Apoe(-/-);ref. 18), singly or combined with a deficiency of t-PA (Apoe(-/-):Plat(-/-)) or of u-PA (Apoe(-/-):Plau(-/-); ref. 19), indicated that deficiency of u-PA protected against media destruction and aneurysm formation, probably by means of reduced plasmin-dependent activation of pro-MMPs. This genetic evidence suggests that plasmin is a pathophysiologically significant activator of pro-MMPs in vivo and may have implications for the design of therapeutic strategies to prevent aortic-wall destruction by controlling Plau gene function

New functions for the matrix metalloproteinases in cancer progression

Matrix metalloproteinases (MMPs) have long been associated with cancer-cell invasion and metastasis. This provided the rationale for clinical trials of MMP inhibitors, unfortunately with disappointing results. We now know, however, that the MMPs have functions other than promotion of invasion, have substrates other than components of the extracellular matrix, and that they function before invasion in the development of cancer. With this knowledge in hand, can we rethink the use of MMP inhibitors in the clinic