Many key physiological processes, including morphogenesis during development, control of cellular proliferation and motility, response to injury, and even survival, require not only the production of ECM, but also its remodeling or degradation. Because of its enormous importance as a key element in the extracellular environment of multicellular organisms, remodeling and degradation of the ECM must be carefully controlled. Degradation of the ECM is often mediated by zinc-dependent ECM metalloproteases. Given the wide array of ECM components, it is not surprising that there are many such metalloproteases with varying substrate specificities and sites of expression. In many cases, their names incorporate the names of their substrates, as for the metalloproteases called collagenases, gelatinases, elastases, and aggrecanases. Some are secreted into the extracellular fluid, and others are closely associated with the plasma membranes of cells, either tightly bound in a noncovalent association with the membrane or as integral membrane proteins. Many are initially synthesized as inactive precursors that must be specifically activated to function.

ECM metalloproteases are divided into three major subgroups based on the enzymes’ structures: matrix metalloproteases (MMPs) (of which there are 23 in humans), a disintegrin and metalloproteinases (ADAMs), and ADAMs with thrombospondin motifs (ADAMTSs). These proteases can degrade ECM components as well as non-ECM components such as adhesion receptors. Indeed, a key function of ADAMs is cleaving extracellular domains from integral membrane proteins. One mechanism used to control the activities of these proteases is the production of protein inhibitors called TIMPs (tissue inhibitors of metalloproteinases) and RECK (reversion-inducing–cysteine-rich protein with kazal motifs). Some of these inhibitors have their own cell-surface receptors and functions independent of their ability to inhibit metalloproteinases. ECM-degrading proteases are associated with a variety of diseases, the best known of which is metastatic (spreading) cancer (see Chapter 24).