| Matrix metalloproteinases(MMPs)are a family of structurally and functionally related zinc-dependent endopeptidases consisting of at least 23 enzymes which are able to degrade all the protein components of the extracellular matrix.In general,MMPs have a signal peptide for secretion,a propeptide containing a cysteine as zinc ligand for maintaining enzyme latency, and a catalytic domain containing three histidines as zinc ligands for enzymatic activity.With the exception of MMP-7,all MMPs possess a haemopexin-like domain in the C-terminus.According to their substrate specificity and structure ,members of the MMP gene family can be classified into subgroups of collagenases,gelatinases, stromelysins,membrane-type MMPs (MT-MMPs),and novel MMPs.MMP-1,-8,and -13 (collagenase-1,-2,and-3) are the principal secreted neutral proteinases capable of initiating degradation of native fibrillar collagens. MMP-2 ( a 72-kDa gelatinase,gelatinase-A ) and MMP-9 ( a 92-kDa gelatinase,gelatinase-B ) were initially called 72-kDa and 92-kDa type IV collagenases,respectively,and they contain fibronectin type II inserts (the FN-like domain) within the catalytic domain,which can promote binding to gelatin and native type I collagen.MMP-2 and -9 are thought to play an important role in the final degradation of fibrillar collagens after they have first been cleaved by collagenases and denatured. MMP-3 and -10 (stromelysin-1 and -2) are closely related with respect to structure and substrate specificity,and they are able to degrade a wide range of substrates.MMP-11 (stromelysin-3),MMP-7 (matrilysin),and MMP-12 (macroph- age metalloelastase) are often included in the stromelysin subgroup.MMP-11 has not been shown to degrade any ECM component,but it degrades serine proteinase inhibitors.MMP-7,the smallest member of the MMP gene family,lacks the haemopexin-like domain.MT-MMPs contain a unique transmembrane domain that anchors the enzymes to the cell surface.MT1-MMP(MMP-14),MT2-MMP(MMP-15)and MT3-MMP(MMP-16)have been shown to activate latent MMP-2 proteolytically,and MT1-MMP and MT2-MMP have also been shown to activate latent MMP-13.Some recently cloned novel human members of the MMP family,MMP-19 initially named MMP-18,and MMP-20,MMP-28,cannot be classified to any of the MMP subgroups on the basis of their structure and substrate specificity.The ability of MMP-19 to degrade native ECM components is not known.MMP-20 is expressed during tooth development and has been shown to degrade amelogenin.Most MMPs are secreted as latent precursors(zymogens),which are proteolytically activated in the extracellular space.The proMMPs are retained in latent form by a'cysteine switch'formed by the interaction of a conserved cysteine in the propeptide with the catalytic zinc blocking the access of the catalytic site to substrate.Activation of the latent MMP by chaotropic agents (eg organo- mercurials),or partial proteolytic cleavage of the propeptide,dissociates the covalent bond between the cysteine and the catalytic zinc and exposes the catalytic site. The proteolytic activity of MMPs is inhibited specifically by tissue inhibitors of metalloproteinases(TIMPs)as well as by nonspecific inhibitors,including the 2-macroglobulin and the 1-antiprotease.In general,MMPs are not constitutively expressed by cells in vivo,but their expression is rapidly induced in response to exogenous signals,eg cytokines or growth factors and altered cell-matrix and cell-cell interactions.The expression of MMPs is primarily regulated at the level of transcription,and their proteolytic activity is regulated by zymogen activation and inhibition of activity. MMPs are key players in many physiological and pathological processes such as development,angiogenesis,connective tissue remodelling, wound heali- ng ,immunity and inflammation,as well as tumour invasion and metastasis.MMPs are believed to promote tumour progression by initiating carcinogene- sis,enhancing tumour angiogenesis,disrupting local tissue architecture to allow tumour growth,and bre...
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