Matrix metalloproteinases , inflammation and atherosclerosis : therapeutic perspectives. (2004 Apr)
matrix metalloproteinases , inflammation and atherosclerosis : therapeutic perspectives . matrix metalloproteinases ( MMPs ) , also called matrixins , are proteinases that participate in extracellular matrix remodelling and degradation . under normal physiological conditions , the activities of MMPs are precisely regulated at the level of transcription , of activation of the pro MMP precursor zymogens and of inhibition by endogenous inhibitors ( tissue inhibitors of metalloproteinases ; timps ) . alteration in the regulation of MMP activity is implicated in diseases such as cancer , fibrosis , arthritis and atherosclerosis . The pathological effects of MMPs and timps in cardiovascular diseases involve vascular remodelling , atherosclerotic plaque instability and left ventricular remodelling after myocardial infarction . since excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic lesion progression ( including plaque disruption ) , MMPs represent a potential target for therapeutic intervention aimed at modification of vascular pathology by restoring the physiological balance between MMPs and timps . This review describes the members of the MMP and TIMP families and discusses the structure , function and regulation of MMP activity ; finally , pharmacological approaches to MMP inhibition are highlighted .

Pathogenesis of bone and cartilage destruction in rheumatoid arthritis. (2003 Jun)
pathogenesis of bone and cartilage destruction in rheumatoid arthritis . proinflammatory cytokines , such as interleukin 1 ( IL 1 ) and tumour necrosis factor alpha ( tnfalpha ) , have been implicated in the dysregulation of bone and cartilage remodelling characteristic of rheumatoid arthritis ( RA ) . With respect to bone remodelling , both of these cytokines have been shown to up regulate the production of the receptor activator of nuclear factor kappab ligand , which acts to enhance osteoclastic bone resorption . tnfalpha stimulates differentiation of osteoclast progenitors into mature osteoclasts and IL 1 acts directly on osteoclasts to increase the bone resorbing capacity of these cells . IL 1 and tnfalpha also adversely affect cartilage remodelling , although IL 1 is more potent on a molar basis . This cytokine not only increases production of factors that stimulate cartilage matrix degradation , but also inhibits the synthesis of type II collagen and proteoglycans . enhanced understanding of the mechanisms underlying the processes of joint destruction will allow more selective and specific application of therapeutic agents that target these proinflammatory cytokines and , thus , more effective management of patients with RA and other inflammatory disorders .

Normal synoviocytes and synoviocytes from osteoarthritis and rheumatoid arthritis bind extracellular matrix proteins differently extracellular matrix proteins are increased in … (1995 Jun)
normal synoviocytes and synoviocytes from osteoarthritis and rheumatoid arthritis bind extracellular matrix proteins differently extracellular matrix proteins are increased in inflammatory synovitis . We showed previously that the in situ expression of the corresponding extracellular matrix receptors ( beta 1 integrins ) is enhanced in synoviocytes ( SC ) of synovitis of different etiology ( 16 ) . To investigate the adhesion of SC to extracellular matrix proteins , we examined the attachment of SC from normal and inflamed synovia to fibronectin , tenascin , laminin and collagen type IV . compared to normal SC and SC of osteoarthritis , SC of rheumatoid arthritis showed an increased binding to tenascin , laminin , fibronectin and collagen type IV , suggesting a distinctive interaction of SC and extracellular matrix proteins in rheumatoid arthritis . furthermore , the increased binding of SC of rheumatoid arthritis to extracellular matrix proteins may play a role in tissue remodelling associated with rheumatoid arthritis .

Matrix metalloproteinases and atherosclerosis. (2003 Apr)
matrix metalloproteinases and atherosclerosis . therapeutic aspects matrix metalloproteinases ( MMPs ) play a key role in the physiology of connective tissue development , morphogenesis and wound healing , but their unregulated activity has been implicated in numerous disease processes including arthritis , tumor cell metastasis and atherosclerosis . MMP family consists of at least 20 members ; MMPs are produced by the different cell types ( vascular smooth muscle cells , monocytes , endothelial cells ) involved in the atheromatous plaque formation and participate to extracellular matrix remodelling and cell infiltration or migration . since excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic lesion progression ( including plaque disruption ) , MMPs represent a potential target for therapeutic intervention to modify vascular pathology , by restoring the MMP / TIMP physiological equilibrium . This review highlights the structures of MMPs and their physiological inhibitors , the tissue inhibitors of MMPs ( timps ) , and describes the current developments in pharmacological MMP inhibition .

Matrix metalloproteinase inhibitors : a review on pharmacophore mapping and ( Q ) SARs results. (2005 Feb)
matrix metalloproteinase inhibitors : a review on pharmacophore mapping and ( Q ) SARs results . The matrix metalloproteinases ( MMPs ) are a family of more than 20 enzymes that are intimately involved in tissue remodelling . these zinc containing endopeptidases consist of several subsets of enzymes , including collagenase , stromelysins and gelatinases and are involved in the degradation of the extracellullar matrix ( ECM ) that forms the connective material between cells and around tissues . disease processes associated with the MMPs are generally related to imbalance between the inhibition and activation of MMPs resulting in excessive degradation of the ECM . these indications include osteoarthritis rheumatoid arthritis , tumour metastasis and congestive heart failure . inhibitors for these enzymes have been developed for the treatment of a starthingly wide array of disease process where matrix remodelling plays a key role . there are three major components to most MMP inhibitors the zinc binding group ZBG , the peptidic backbone and the pocket occupying side chain . Most MMPs inhibitors are classified according to their ZBG . inhibitors interactions at active site zinc plays a critical role in defining the binding mode and relative inhibitor potency . The majority of MMP inhibitors reported in the literature contain an effective zinc binding group ( e . g . hydroxamic acid , carboxylic acid , sulfhydryl group ) that is either generally substituted with a peptide like structure that mimics the substrates that they cleave or appended to smaller …

Matrix metalloproteinases and tissue inhibitors of metalloproteinases in the pathogenesis of rheumatoid arthritis rheumatoid arthritis ( RA ) is a … (2006 May)
matrix metalloproteinases and tissue inhibitors of metalloproteinases in the pathogenesis of rheumatoid arthritis rheumatoid arthritis ( RA ) is a chronic inflammatory disorder of joints characterized by the accumulation of mononuclear cells and the proliferation of the synovium lining layer . The role of lymphocytes , macrophages and fibroblasts infiltrating the synovium is not fully understood . these cells are supposed to be involved in the tissue destruction by several mechanisms , including the production of proinflammatory cytokines and matrix metalloproteinases . matrix metalloproteinases ( MMPs ) are the enzymes that participate in the proteolytic degradation and remodelling of the extracellular matrix . their action is controlled by tissue inhibitors of metalloproteinases ( timps ) . In this review we describe the role of metalloproteinases and their tissue inhibitors in the pathogenesis of rheumatoid arthritis .

Matrix metalloproteinases in the progression of heart failure : potential therapeutic implications. (2001 Aug)
matrix metalloproteinases in the progression of heart failure : potential therapeutic implications . matrix metalloproteinases ( MMPs ) are a family of functionally related zinc containing enzymes that denature and degrade fibrillar collagens and other components of the extracellular matrix . myocardial extracellular matrix remodelling and fibrosis regulated by MMPs are believed to be important contributors to the progression of heart failure . The role of MMPs in cardiac fibrosis and the progression of heart failure , along with the possibility of halting the progression of heart failure by modulating extracellular matrix remodelling are important issues under intense study . MMPs are increased in the failing hearts of both animal models and patients with heart failure . MMP inhibition may therefore modulate extracellular matrix remodelling and the progression of heart failure . It is a great advantage that various MMP inhibitors have been developed initially for the treatment of cancer , arthritis and other diseases believed to be associated with increased MMP activity . several preclinical studies have shown that treatment of heart failure in animal models with MMP inhibitors results in less collagen matrix damage , favourable extracellular matrix remodelling , and improved cardiac structure and function . The results suggest that modulation of MMP activity can prevent myocardial dysfunction and the progression of heart failure through alterations in the remodelling process of extracellular matrix and the left ventricle . although these promising results suggest potential benefits of MMP inhibition for human heart failure , no clinical data evaluating …

Matrix metalloproteinases : their biological functions and clinical implications. (2005 Jul)
matrix metalloproteinases : their biological functions and clinical implications . matrix metalloproteinases ( MMPs ) , which are also known as matrixins , are proteinases that participate in extracellular matrix remodelling and degradation . under normal physiological conditions , the activities of MMPs are precisely regulated at the level of transcription , at that of activation of the pro MMP precursor zymogenes as well as at that of inhibition by endogenous inhibitors ( tissue inhibitors of metalloproteinases , timps ) . alterations in the regulation of MMP activity are implicated in diseases such as cancer , fibrosis , arthritis and atherosclerosis . The pathological effects of MMPs and timps in cardiovascular diseases involve vascular remodelling , atherosclerotic plaque instability and cardiac remodelling in congestive heart failure or after myocardial infarction . since excessive tissue remodelling and increased matrix metalloproteinases activity have been demonstrated during atherosclerotic lesion progression ( including plaque disruption ) , MMPs represent a potential target for therapeutic intervention aimed at the modification of vascular pathology by restoring the physiological balance between MMPs and timps . recent findings suggest that MMPs are also involved in cancer initiation , invasion and metastasis ; MMP inhibitors could be considered for evaluation as cancer chemopreventive molecules . This review describes the members of MMP and TIMP families and discusses the structure , function and regulation of MMP activity . ( Tab . 1 , Ref : 45 . )

Matrix metalloproteinases : useful and deleterious. (2007 Jul)
matrix metalloproteinases : useful and deleterious . MMPs ( matrix metalloproteinases ) are zinc dependent endopeptidases that degrade both matrix and non matrix proteins . They play an important role in morphogenesis , and in a wide range of processes including tissue repair and remodelling . their abnormal expression contributes to pathological processes including arthritis , cancer , and cardiac and central nervous system diseases , which explains the large interest in finding specific MMP inhibitors for therapeutic use . In this review we describe the structural features of MMPs , with special emphasis on their interaction with specific inhibitors . The effect of new , hydroxamatebased inhibitors on MMP isolated from bovine brain is evaluated .

Metalloproteinases and neurovascular injury matrix metalloproteinases ( MMP ) are a family of proteases involved in the remodelling of the … (2004 Jun)
metalloproteinases and neurovascular injury matrix metalloproteinases ( MMP ) are a family of proteases involved in the remodelling of the extracellular matrix . In physiological conditions , the activity of MMP is regulated on several levels : gene transcription , activation of inactive precursors , and inhibition by endogenous factors . Loss of control and increased expression and activity of MMP have been implicated in various diseases ( cancer , arthritis , vascular aneurysms , atherosclerosis , etc . ) . In the central nervous system , MMP are involved in the mechanisms associated with neuroinflammation , which is different in vascular and non vascular diseases . MMP , especially MMP 9 , have been shown to induce a high breakdown capacity , especially in the arteriolar basement membrane , leading to cerebral edema and secondary hemorrhage . In human clinical aspects , MMP are associated to intracerebral hemorrhage growth and with the development of complications in ischemic stroke . combination therapies explicitly involving MMP inhibition could be of value in future treatment strategies .

Collagenase unwinds triple helical collagen prior to peptide bond hydrolysis. (2004 Aug)
collagenase unwinds triple helical collagen prior to peptide bond hydrolysis . breakdown of triple helical interstitial collagens is essential in embryonic development , organ morphogenesis and tissue remodelling and repair . aberrant collagenolysis may result in diseases such as arthritis , cancer , atherosclerosis , aneurysm and fibrosis . In vertebrates , it is initiated by collagenases belonging to the matrix metalloproteinase ( MMP ) family . The three dimensional structure of a prototypic collagenase , MMP 1 , indicates that the substrate binding site of the enzyme is too narrow to accommodate triple helical collagen . Here we report that collagenases bind and locally unwind the triple helical structure before hydrolyzing the peptide bonds . mutation of the catalytically essential residue glu200 of MMP 1 to Ala resulted in a catalytically inactive enzyme , but in its presence noncollagenolytic proteinases digested collagen into typical 3 / 4 and 1 / 4 fragments , indicating that the MMP 1 ( e200a ) mutant unwinds the triple helical collagen . The study also shows that MMP 1 preferentially interacts with the alpha2 ( I ) chain of type I collagen and cleaves the three alpha chains in succession . Our results throw light on the basic mechanisms that control a wide range of biological and pathological processes associated with tissue remodelling .

The chitinase 3 like protein human cartilage glycoprotein 39 inhibits cellular responses to the inflammatory cytokines interleukin 1 and tumour … (2004 Jun)
The chitinase 3 like protein human cartilage glycoprotein 39 inhibits cellular responses to the inflammatory cytokines interleukin 1 and tumour necrosis factor alpha . expression of the chitinase 3 like protein HC gp39 ( human cartilage glycoprotein 39 ) is associated with conditions of increased matrix turnover and tissue remodelling . High levels of this protein have been found in sera and synovial fluids of patients with inflammatory and degenerative arthritis . In order to assess the role of HC gp39 in matrix degradation induced by inflammatory cytokines , we have examined its effect on the responses of connective tissue cells to TNF alpha ( tumour necrosis factor alpha ) and IL 1 ( interleukin 1 ) with respect to activation of signalling pathways and production of MMPs ( matrix metalloproteases ) and chemokines . stimulation of human skin fibroblasts or articular chondrocytes with IL 1 or TNF alpha in the presence of HC gp39 resulted in a marked reduction of both p38 mitogen activated protein kinase and stress activated protein kinase / Jun N terminal kinase phosphorylation , whereas nuclear translocation of nuclear factor kappab proceeded unimpeded . HC gp39 suppressed the cytokine induced secretion of MMP1 , MMP3 and mmp13 , as well as secretion of the chemokine IL 8 . The suppressive effects of HC gp39 were dependent on phosphoinositide 3 kinase activity , and treatment of cells with HC gp39 resulted in AKT mediated serine / threonine phosphorylation of apoptosis signal regulating kinase 1 . This …

1. (1997 Aug)
1 . 8 A crystal structure of the catalytic domain of human neutrophil collagenase ( matrix metalloproteinase 8 ) complexed with a peptidomimetic hydroxamate primed side inhibitor with a distinct selectivity profile . matrix metalloproteinases ( MMP ) are zinc endopeptidases involved in tissue remodelling . They have been implicated in a series of pathologies , including cancer , arthritis , joint destruction and alzheimer s disease . human neutrophil collagenase represents one of the three interstitial collagenases that cleave triple helical collagen of type I , II and III . Its catalytic domain ( residues phe79 gly242 ) has been heterologously expressed in escherichia coli and crystallized as a non covalent complex with the hydroxamate inhibitor BB 1909 , which has distinct selectivity against different MMP , in a crystal form . The crystal structure , refined to 0 . 18 nm resolution , shows that BB 1909 is a right hand side inhibitor that binds to the S1 S3 subsites and coordinates to the catalytic Zn2 in a bidentate manner via the hydroxyl and carbonyl oxygen atoms of the hydroxamate group in a similar manner to batimastat . The collagenase / BB 1909 complex is described in detail and compared with the collagenase / batimastat complex . these studies provide information on MMP specificity and thus may assist the development of more selective MMP inhibitors .

Structure and function of matrix metalloproteinases and timps. (2006 Jan)
structure and function of matrix metalloproteinases and timps . matrix metalloproteinases ( MMPs ) , also called matrixins , function in the extracellular environment of cells and degrade both matrix and non matrix proteins . They play central roles in morphogenesis , wound healing , tissue repair and remodelling in response to injury , e . g . after myocardial infarction , and in progression of diseases such as atheroma , arthritis , cancer and chronic tissue ulcers . They are multi domain proteins and their activities are regulated by tissue inhibitors of metalloproteinases ( timps ) . This review introduces the members of the MMP family and discusses their domain structure and function , proenyme activation , the mechanism of inhibition by timps and their significance in physiology and pathology .

Crystal structure of an active form of human MMP 1. (2006 Aug)
crystal structure of an active form of human MMP 1 . The extracellular matrix is a dynamic environment that constantly undergoes remodelling and degradation during vital physiological processes such as angiogenesis , wound healing , and development . unbalanced extracellular matrix breakdown is associated with many diseases such as arthritis , cancer and fibrosis . interstitial collagen is degraded by matrix metalloproteinases with collagenolytic activity by MMP 1 , MMP 8 and MMP 13 , collectively known as the collagenases . matrix metalloproteinase 1 ( MMP 1 ) plays a pivotal role in degradation of interstitial collagen types I , II , and III . Here , we report the crystal structure of the active form of human MMP 1 at 2 . 67 A resolution . This is the first MMP 1 structure that is free of inhibitor and a water molecule essential for peptide hydrolysis is observed coordinated with the active site zinc . comparing this structure with the human prommp 1 shows significant structural differences , mainly in the relative orientation of the hemopexin domain , between the pro form and active form of the human enzyme .

Analysis of 16 different matrix metalloproteinases ( MMP 1 to MMP 20 ) in the synovial membrane : different profiles … (1999 Dec)
analysis of 16 different matrix metalloproteinases ( MMP 1 to MMP 20 ) in the synovial membrane : different profiles in trauma and rheumatoid arthritis . objective : To define the pattern of mRNA expression of all human matrix metalloproteinases ( MMPs ) described to date in rheumatoid arthritis ( RA ) and traumatic synovial membrane , in order to differentiate between a physiological tissue remodelling pattern and that associated with inflammatory tissue destruction . methods : analysis of swissprot protein and EMBL / genbank nucleotide sequence banks , protein sequence alignment , reverse transcriptase polymerase chain reaction and nucleotide sequencing were used . results : MMP 2 ( gelatinase A ) , MMP 3 ( stromelysin 1 ) , MMP 11 ( stromelysin 3 ) and MMP 19 were constitutively expressed . MMP 1 ( fibroblast type collagenase ) , MMP 9 ( gelatinase B ) and MMP 14 ( MT1 MMP ) were expressed in all RA , but only in 55 80 of trauma samples . MMP 13 ( collagenase 3 ) and MMP 15 ( MT2 MMP ) were expressed exclusively in RA ( 80 90 of the samples ) . MMP 20 ( enamelysin ) was absent and MMP 8 ( collagenase 2 ) was rarely found in RA or trauma . All other MMPs ( 7 , 10 , 12 , 16 , 17 ) had an intermediate pattern of expression . conclusions : Some MMPs without interstitial collagenase activity seem to have a …

Proteinases in rheumatoid arthritis. (1992 Jul)
proteinases in rheumatoid arthritis . The role of proteinases in the extracellular breakdown of the connective tissue matrix during disease processes is outlined . focussing on the matrix metalloproteinases , we present an overview of the mechanisms regulating their activity . methods of assessing their role in disease processes is exemplified by new data on stromelysin activity in remodelling joint tissues in both model systems and human disease .

TSG 6 : a multifunctional protein associated with inflammation. (2003 Apr)
TSG 6 : a multifunctional protein associated with inflammation . TSG 6 expression is upregulated in many cell types in response to a variety of proinflammatory mediators and growth factors . This protein is detected in several inflammatory disease states ( e . g . rheumatoid arthritis ) and in the context of inflammation like processes , such as ovulation , and is often associated with extracellular matrix remodelling . TSG 6 has anti inflammatory and chondroprotective effects in various models of inflammation and arthritis , which suggest that it is a component of a negative feedback loop capable of downregulating the inflammatory response . growing evidence also indicates that TSG 6 acts as a crucial factor in ovulation by influencing the expansion of the hyaluronan rich cumulus extracellular matrix in the preovulatory follicle . TSG 6 is a member of the Link module superfamily and binds to hyaluronan ( a vital component of extracellular matrix ) , as well as other glycosaminoglycans , via its Link module . In addition , TSG 6 forms both covalent and non covalent complexes with inter alpha inhibitor ( a serine protease inhibitor present at high levels in serum ) and potentiates its anti plasmin activity .

Polymorphism in matrix metalloproteinase gene promoters : implication in regulation of gene expression and susceptibility of various diseases. (2001 Jan)
polymorphism in matrix metalloproteinase gene promoters : implication in regulation of gene expression and susceptibility of various diseases . The matrix metalloproteinases ( MMPs ) can degrade a range of extracellular matrix proteins and have been implicated in connective tissue destruction and remodelling associated with cancer invasion and metastasis , cartilage destruction in arthritis , atherosclerotic plaque rupture , and the development of aneurysms . recently , naturally occurring sequence variation has been detected in the promoter of a number of MMP genes . these genetic polymorphisms have been shown to have allele specific effects on the transcriptional activities of MMP gene promoters , and to be associated with susceptibility to coronary heart disease , aneurysms and cancers . these findings indicate that variation in the MMP genes may contribute to inter individual differences in susceptibility to these common , complex diseases , likely through effects on the balance between the synthesis and degradation of extracellular matrix proteins .

Matrix metalloproteases : variations on a theme. (1998 Nov)
matrix metalloproteases : variations on a theme . The family of proteins called matrix metalloproteinases ( MMPs ) are a class of structurally related proteins that are collectively responsible for the metabolism of extracellular matrix proteins . these zinc and calcium dependent enzymes , which include the collagenases , stromelysins and gelatinases , are involved in normal tissue remodelling processes such as wound healing , pregnancy and angiogenesis . under physiological conditions , in addition to the regulated proteolyses of inactive precursors to the active form , the degradative nature of these enzymes are precisely controlled by endogenous inhibitors ( timps ) . The excess syntheses and production of these proteins lead to the accelerated matrix degradation associated with diseases such as arthritis , cancer and multiple sclerosis . The MMPs have therefore proved to be attractive targets for structure based drug design . The pursuit of low molecular weight inhibitors of these proteins have encouraged structural studies on several members of family , so that the molecular details of enzyme inhibitor interactions of the MMPs have become available . these studies provide insights into the basic structural framework of the MMP superfamily and reveal characteristics which promote specificity between individual members . The analyses of the three dimensional structure of the MMPs in the context of their primary sequence and the design and selectivity of low molecular weight inhibitors of the superfamily is the subject of this review .