Inhibition of Matrix Metalloproteases

Metalloproteinases (MMP) play a key role in the response of cells to their microenvironment. By affecting proteolytic degradation or activation of cell surface and extracellular matrix (ECM) proteins, they modulate both cell-cell and cell-ECM interactions which in turn influence cell differentiation, migration, proliferation and survival. MMPs are endopeptidases belonging to the metzincin super family, which depend on the presence of zinc for their catalytic activity. The MMP family consists of at least 26 known members, which are grouped according to their substrate specificity. The collagenases (MMP-1, -8 and -13) degrade fibrillar forms of interstitial collagen. The gelatinases (MMP-2 and -9) are specific for denatured collagens and collagen-IV of the basement membrane. Stromelysins (MMP-3, -10 and -11) primarily cleave non-collagen components of ECM such as fibronectin, laminin and vitronectin. MT-MMPs (MMP-14, -15, -16, -17 and -24) are membrane-type MMPs found on the surface of many cell types. Other MMPs include matrilysins (MMP-7 and -26), metalloelastase (MMP-12), enamelysin (MMP-20), and other MMPs with less defined characteristics. In addition to MMPs, the metzincin super family also contains ADAM cell surface transmembrane proteins.MMPs are tightly regulated at multiple levels, including 1) gene transcription 2) activation of the latent enzyme and 3) inactivation by specific inhibitors. TIMPs form a group of MMP regulators. Four TIMPs have been identified (TIMP1, TIMP2, TIMP3, and TIMP4), each with its own physiologic role. TIMP1, TIMP2 and TIMP4 are found in a soluble form, while TIMP3 is anchored to the ECM by binding to heparan-sulphate-containing proteoglycans and possibly chondroitin-sulphate-containing proteoglycans. All four TIMPs inhibit active forms of MMPs. The common thread within this family of enzymes is their ability to form non-covalent bonds with the latent and active forms of MMPs with a 1:1 stoichiometry. Pro-MMP2 binds to MT-MMP1 and TIMP2 and forms a complex on the cell surface, which acts as a substrate for a second MT-MMP1 molecule. The result is cleavage of the pro-MMP2 to produce the active form. This complex formation intimately associates MMP2 with the cell surface, potentially involving it in the process of cell invasion. MMPs are inhibited nonspecifically via their association with α2-macroglobulin. MMPs cannot bind to their substrates and are readily cleared by endocytosis through the low density LDL-RP via a TSP2 complex. Other inhibitors such as RECK, a GPI -anchored glycoprotein, bind and inhibit a number of MMPs. RECK inhibition of MMPs inhibits various MMP functions including invasion of tissues, metastasis and tumor angiogenesis and is essential for normal development.Deregulation of MMPs has been implicated in diverse cardiovascular diseases, development and rupture of aneurysms, restenosis following balloon angioplasty and the failure of vein grafts following coronary artery bypass graft failure. MMPs and TIMPs also contribute to the pathogenesis of asthma via their influence on the function and migration of inflammatory cells as well as matrix deposition and degradation.