Matrix metalloproteinases: effectors of development and normal physiology

Abstract

The matrix metalloproteinase (MMP) family of extracellular proteinases regulates development and physiologic events. Genetic analyses using transgenic mice that have gain and loss of function of MMPs or of their endogenous inhibitors, the TIMPs, and pharmacogenetic studies with chemical inhibitors have begun to elucidate the roles that they play. It is now clear that these enzymes are important for cell migration, invasion, proliferation, and apoptosis. They regulate many developmental processes, including branching morphogenesis, angiogenesis, wound healing, and extracellular matrix degradation. The matrix metalloproteinases (MMPs) are a family of extracellular matrix (ECM)-degrading enzymes that shares common functional domains and activation mechanisms (Sternlicht et al. 2000). These are Caand Zn-dependent endopeptidases that are active at neutral pH. They are synthesized as secreted or transmembrane proenzymes and processed to an active form by the removal of an amino-terminal propeptide. The propeptide is thought to keep the enzyme in latent form by the interaction of a cysteine residue in this peptide with the zinc moiety in the enzyme active site. Disruption of this interaction triggers the cysteine switch mechanism and results in activation of the enzyme. MMPs can be activated by chaotropic agents or by cleavage of the propeptide by members of the MMP family or by other proteases. They are inhibited by a family of tissue inhibitors of metalloproteinases, the TIMPs. As a family, MMPs degrade most components of the ECM. There are now >20 members of the MMP family. There are several distinct subgroups based on preferential substrates or similar structural domains: Collagenases that are active against fibrillar collagen, gelatinases that have high activity against denatured collagens, stromelysins that degrade noncollagen components of the ECM, membranetype MMPs (MT-MMPs) that are transmembrane molecules, and other less characterized members (Fig. 1; Table 1). Because MMPs can degrade ECM molecules, their main function has been presumed to be remodeling of the ECM. They are thought to play important roles during embryonic development, as ECM remodeling is a critical component of tissue growth and morphogenesis. In fact, the discovery of MMPs was based on the observation that during amphibian metamorphosis, a collagenolytic activity has to be present to digest the collagens in tadpole tails (Gross and Lapiere 1962). The activity of MMPs during embryonic development may extend to more than the removal of unwanted ECM molecules, however. It is now clear that MMPs not only remodel the ECM, but also influence many cellular functions. MMP activity may be required during development and normal physiology in several ways: (1) to degrade ECM molecules and allow cell migration; (2) to alter the ECM micro-environment and result in alteration in cellular behavior; (3) to modulate the activity of biologically active molecules by direct cleavage, release from bound stores, or the modulating of the activity of their inhibitors (Fig 2). During tissue morphogenesis any number of these activities may contribute to the role that each MMP plays in a developmental process. Although insights into the activities of MMPs have emerged from in vitro studies, genetic and pharmacogenetic studies now indicate that MMPs do have important influence on many cellular functions. Two general approaches have been employed to identify the roles of MMPs during mammalian development: (1) general or tissue-specific expression of a transgene encoding an MMP or an MMP inhibitor (TIMP), and (2) generating null mutations in an MMP gene or TIMP gene using targeted mutagenesis. These approaches have given insights into the roles of several MMPs in development and normal physiology. The range of developmental effects seen in these function perturbation studies suggests that these enzymes do indeed participate as essential effectors of developmental processes in vivo.