A confederacy of proteinases.

The demolition of large buildings can be accomplished by a single explosive agent destroying a single class of structural components, namely weightbearing beams. Although the breakdown of tissues in disease has often been conceived to occur in an analogous manner, with a single proteinase degrading a single structural ECM protein, it has become clear that effective tissue destruction requires several proteinases acting on diverse substrates. For example, the destruction of articular cartilage in osteoarthritis involves the degradation of aggrecan, type II collagen, and other matrix components by many different enzymes produced by a variety of cell types (1). In this issue of the JCI, Longo et al. (2) extend this concept to vascular disease, reporting that aneurysm formation in mice requires the activity of at least two matrix metalloproteinases (MMPs), gelatinase-A (MMP-2) and gelatinase-B (MMP-9), released by different cell types. The hallmark pathology of abdominal aortic aneurysms is the destruction of medial elastic lamellae. Because lamellae are the main structural component of large arteries, it is reasonable that their breakdown, coupled with continuous arterial pressure, would lead to vessel expansion and, eventually, rupture. Elastic lamellae are made principally of elastic fibers, and elastic fibers are composed primarily of elastin, as well as microfibrillar and other proteins (3). Thus, elastases, the proteinases that can degrade elastin, have been targeted as the destructive agents in aneurysms. Of the various classes of elastases, the metallo-elastases are prominently expressed in human aneurysms and have been the most studied group of matrix-degrading proteinases in aneurysm research (4, 5). Indeed, animal studies provide compelling evidence that one class of MMP, the metallo-gelatinases (6), includes destructive agents important for the pathogenesis of aneurysm formation. Clinical studies are ongoing to assess the efficacy of MMP inhibitors in halting progression of asymptomatic aortic aneurysms (7). Two years ago, Thompson and coworkers reported that aneurysm formation is blocked in gelatinase-B knock-out mice but not in macrophage metallo-elastase–deficient (MMP-12– deficient) mice (8). Using a slightly different model, Longo et al. (2) also find that aneurysms do not form in gelatinase-B–null deficient mice. Because gelatinase-B in aneurysms is a product of inflammatory cells, primarily macrophages (9), it is reassuring that both groups verified that inflammation in the injured aortic wall was not affected by a lack of this MMP. Both groups also restored aortic expansion in gelatinase-B–null mice with a bone marrow transplant from wild-type mice, thus demonstrating the importance of inflammatory cell-derived gelatinase-B. Longo et al. further showed that gelatinase-A–null mice do not develop aneurysms following aortic injury. In the vessel wall, as in most tissues, gelatinase-A is expressed primarily by resident mesenchymal cells, specifically medial smooth muscle cells (10). Indeed, bone marrow from wild-type mice did not restore aneurysm formation in gelatinase-A knock-out mice (2). These are interesting findings, particularly to one with a proteinase-centric view of the world, since they suggest that the gelatinases act on different substrates. However, these data do not demonstrate that either gelatinase has degraded the elastin in the vessel wall. As their name suggests, MMPs are thought to be responsible for the turnover and degradation of connective tissue proteins, a function clearly performed by several family members. However, matrix degradation is not the sole function of these enzymes. Several reports from recent years have suggest-