Abstract

The matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. There are at least 23 members of MMPs ever reported in human, and they and their substrates are widely expressed in many tissues. Recent growing evidence has established that MMP not only can degrade a variety of components of extracellular matrix, but also can cleave and activate various non-matrix proteins, including cytokines, chemokines and growth factors, contributing to both physiological and pathological processes. In normal conditions, MMP expression and activity are tightly regulated via interactions between their activators and inhibitors. Imbalance among these factors, however, results in dysregulated MMP activity, which causes tissue destruction and functional alteration or local inflammation, leading to the development of diverse diseases, such as cardiovascular disease, arthritis, neurodegenerative disease, as well as cancer. This article focuses on the accumulated evidence supporting a wide range of roles of MMPs in various non-neoplastic diseases and provides an outlook on the therapeutic potential of inhibiting MMP action.

Highlights

  • Matrix metalloproteinases (MMPs, known as matrixins) are secreted or membrane-bound endopeptidases belonging to the metzincin superfamily

  • The aim of this review is to summarize the accumulated knowledge about the matrix metalloproteinases (MMPs), when necesTshaeryaaimddoefdtwhiisthreAvDieAwMiss taondsuAmDmAaMrizTeSst,hdeiasccucussminuglathteedirksntrouwctluerdegse, faubnocutitonths,erMegMulPatsi,own hanend npeacthesoslaorgyicaadl droeldeswiniththAe DcoAmMmsoannndoAnD-nAeoMpTlaSssti,cddisiscoursdsienrgs. tShienicrestthruecotvuerer-se,xfpurnecstsiioonns,arnedgudleattriiomneanntadl proaltehsoloofgiMcaMl rPosleisnincathnececromhamvoenbneoenn-nexetoepnlsaisvtieclydirseovrdieewrse.dSi[n3c–e5]th, ethoeveisrs-euxepirsesbseioynonadndthdeetsricmopeentoalf rtohliesspoapf eMr.MPs in cancer have been extensively reviewed [3,4,5], the issue is beyond the scope of this paper

  • MMP-3 deficiency enlarged atherosclerotic plaque size in the same mice model [49]. These findings suggest that both activities of MMP-1 and -3 may have protective effects against plaque formation by the degradation of matrix components

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Summary

Introduction

Matrix metalloproteinases (MMPs, known as matrixins) are secreted or membrane-bound endopeptidases belonging to the metzincin superfamily. Other members of the superfamily are adamlysins, including a proteinase with a disintegrin and metalloproteinases (ADAMs), ADAM with thrombospondin-like motifs (ADAMTSs), astacins, serralysins and pappalysins. As their names indicate, these enzymes contain zinc ions in their structure, which are needed to carry out the hydrolysis of protein substrates. In the past few years, a growing number of non-matrix substrates for MMPs, including cytokines/chemokines, growth factors, antimicrobial peptides, signaling receptors and other membrane proteins, have been uncovered. MMPs can activate or mediate the functions of these proteins not solely as proteinases, but rather as extracellular processing enzymes. UUnnttiill nnooww,, 2233 ddiissttiinncctt pprrootteeiinnaasseess hhaavvee bbeeeenn iiddeennttiififieedd aass tthhee mmeemmbbeerrss ooff tthhee MMMMPP ffaammiillyy iinn hhuummaann[[11]]. Oprtohleirnwe-irsiec,hthheinggeleartiengaisoens acnondtaaiCn -atesremrieinsaolfhthemreeopfiebxrionn-elickteindtoympeaiInI ,rewpheiacths finusnecrttieodnsinintshuebcstartaatleytrieccodgonmitaiionn, [w9]h.iOchthaelrlowwiseth, tehaebgileiltaytitnoasbeisndcocnotlaliangeansearnieds doef nthartueerefidbrcoonlleacgteinn t(ygpeleatIiInr)e[p1e0a]t.sAilnthseorutegdhimn othsteMcaMtaPlystiacredosemcraeinte,dwmhioclhecaullloews, MthTe-aMbMilitPystaorebilnodcacloizleladgoenn tahnedcdelelnsautrufraecde caonlclhagoreend(gbeylaatisni)n[g1l0e]-.pAaslsthtoraungshmmemosbtrManMe Pdsomaraeinsefcorelltoewdemdobleycualsehs,oMrt Tc-yMtoMplPassmarice ltoacilaolirzebdyoanGthPeI clienlkl asugerfa[1c1e]a. nMchMoPre-d23bhyaassuinngiqleu-epafsesatturarenss,mseumchbraasnaendoammainino-ftoelrlmowineadl bsiygnaaslhaonrtchcyotro, pwlahsimchictatargileotsr bMyMaPG-2P3I tlointkhaegcee[l1l 1m].eMmbMraPn-2e3, ahcayssuteniinqeu-reicfeharteugrieosn, sauncdhaans iamnmamuninoog-ltoebrumliinn-alilkseigdnoaml aaninchinorp, lwacheicohf ttharegheetsmMopMexPi-n2-3litkoetdhoemcealilnm. embrane, a cysteine-rich region and an immunoglobulin-like domain in place of the hemopexin-like domain

Substrate Specificity and Function
Regulation of MMP Expression and Activity
ADAMs and ADAMTSs
Atherosclerosis
Abdominal Aortic Aneurysm
Joint Disorders
Osteoarthritis
Rheumatoid Arthritis
Neurodegenerative Diseases
Multiple Sclerosis
Parkinson’s Disease
Alzheimer’s Disease
Liver Fibrosis
Inflammatory Bowel Diseases
Renal Disorders
Acute Kidney Injury
Chronic Kidney Disease
Diabetic Nephropathy
Respiratory Disorders
Pulmonary Emphysema
Interstitial Pulmonary Fibrosis
Asthma
Tuberculosis
Therapeutic Implications
Conclusions

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