Inhibition of Matrix Metalloproteinases
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Inhibition of Matrix Metalloproteinases
MPs (Metalloproteinases) play key roles in the responses of cells to their microenvironment. By effecting proteolytic degradation or activation of cell surface and ECM (Extracellular Matrix) proteins they can modulate both cell-cell and cell-ECM interactions, which influence cell differentiation, migration, proliferation and survival. Both secreted and membrane bound forms of metalloproteinases have been implicated in pericellular proteolysis, including the MMPs (Matrix Metalloproteinases), the adamalysin-like proteinases with both metalloproteinase and disintegrin-like domains (ADAMs and their counterparts that have a thrombospondin-1-like domain, ADAM-TSs) and the Astacins (Ref.1). MMPs are endopeptidases belonging to the metzincin super family, which depend on the presence of a zinc ion for their catalytic activity. The MMP family contains at least 26 known members, which are grouped according to their substrate specificity. The collagenases (MMP1 , MMP8 , and MMP13 ) degrade fibrillar forms of interstitial collagen. The gelatinases (MMP2 and MMP9) are specific for denatured collagens and collagen-IV of the basement membrane. Stromelysins (MMP3, MMP10, and MMP11) primarily cleave noncollagen components of ECM such as fibronectin, laminin, and vitronectin. MT-MMPs (MMP14, MMP15, MMP16, MMP17, and MMP24) are membrane-type MMPs found on the surface of many cell types. Other MMPs include matrilysins (MMP7 and MMP26), metalloelastase (MMP12), enamelysin (MMP-20), and other MMPs with less defined characteristics. In addition to MMPs, the metzincin super family also contains cell surface transmembrane proteins; ADAM (Ref.2).

MMPs are tightly regulated at multiple levels, including 1) gene transcription, 2) activation of the latent enzyme, and 3) inactivation by specific inhibitors. With the exception of MMP2, which is produced constitutively (Ref.3), gene transcription of MMPs is induced by soluble factors, including cytokines and growth factors, and by integrin-mediated signaling through cell-matrix or cell-cell interactions. Transcriptional activation is dependent on the binding of heterodimers of c-Fos and c-Jun proto-oncogene products to the Activator Protein-1 site. This association allows for maximal activation of the promoters of the inducible MMPs (MMP1, MMP3, MMP7, MMP9, MMP10, MMP12, and MMP13). Once secreted, MMPs must be activated to remove a pro-peptide domain that blocks access to the catalytic site. Activation of the latent protein requires disruption of the bond between the cysteine residue in the pro-domain and zinc ion in the catalytic domain and removal of the pro-peptide. Proteases such as trypsin, plasmin, plasminogen activators, and elastase as well as other MMPs participate in this process, thus promoting autocatalytic cleavage of the pro-MMP to form active MMP. Pro-MMP11 can also be activated intracellularly by the Golgi-associated proteinase, furin.

Another example of MMP activity induction is the complex activation of MMP2, which involves MT-MMP1 (Membrane-Type-1-MMP) at the cell surface. This interaction requires TIMP2 (Tissue Inhibitor of Metalloproteinases-2), to bind to and inactivate MT-MMP1. TIMPs are smaller (22-30 KDa), naturally occurring proteins capable of binding and inactivating MMPs. 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 (Ref.4). All four TIMPs inhibit active forms of all MMPs. The common thread within this family of enzymes is their ability to form noncovalent bonds with the latent and active forms of MMPs with a 1:1 stoichiometry. Pro-MMP2 bind to MT-MMP1 and TIMP2 and form a complex on the cell surface, which acts as a substrate for a second MT-MMP1 molecule. The result is cleavage of the propeptide of 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 (Ref.5). Further regulation of MMPs occurs via binding of inhibitors to the active enzyme. MMPs are inhibited nonspecifically via their association with Alpha2M (Alpha2-Macroglobulin). The proteinase inhibitor Alpha2M, although very large, has some access to the pericellular space in vascularised tissues and once complexed with it, MMPs cannot bind to substrate and are readily cleared by endocytosis through the low density LDL-RP (Lipoprotein Receptor-related Protein) via a TSP2 (Thrombospondin-2) complex. The TFPI2 (Tissue Factor Pathway Inhibitor-2) has also been described as an MMP binding agent. Other inhibitors like RECK (Reversion inducing Cysteine rich protein with Kazal motifs), which is a GPI (Glucose Phosphate Isomerase)-anchored Glycoprotein binds and inhibits a number of MMPs. The inhibition of MMPs by RECK inhibits invasion of tissues, metastasis and tumor angiogenesis, and is essential for normal development. RECK expression is inhibited by Ras(Ref.6).

Deregulation of MMPs has been implicated in diverse cardiovascular diseases including acute and chronic. These include atherosclerosis, myocardial infarction and heart failure, development and rupture of aneurysms, restenosis following balloon angioplasty and the failure of vein grafts following coronary artery bypass graft failure (Ref.7). MMPs and their inhibitors, TIMP 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. Apart from their role in acute airway inflammation, MMPs may contribute to features of airway remodeling including reorganization of matrix, angiogenesis, and smooth muscle hyperplasia. Recently MT1-MMP expression has been reported to correlate with the malignancy of multiple tumor types including lung, gastric, colon, breast, cervical carcinomas, gliomas and melanomas and is an important mediator of cell migration and invasion.