Matrix metalloproteinases as modulators of inflammation and innate immunity

Matrix metalloproteinases (MMPs) were discovered because of their role in amphibian metamorphosis, yet they have attracted more attention because of their roles in disease. Despite intensive scrutiny in vitro, in cell culture and in animal models, the normal physiological roles of these extracellular proteases have been elusive. Recent studies in mice and flies point to essential roles of MMPs as mediators of change and physical adaptation in tissues, whether developmentally regulated, environmentally induced or disease associated.The founding member of the matrix metalloproteinase (MMP) family, collagenase, was identified in 1962 by Gross and Lapiere, who found that tadpole tails during metamorphosis contained an enzyme that could degrade fibrillar collagen 1,2 . Subsequently, an interstitial collagenase, collagenase-1 or MMP1, was found in diseased skin and synovium 3 . In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775-Ile776 or Gly775-Lys776 in native type I, II or III collagen molecules 3,4 . Further research led to the discovery of a family of structurally related proteinases (23 in human, 24 in mice), now referred to as the MMP family.Interest in MMPs increased in the late 1960s and early 1970s following observations that MMPs are upregulated in diverse human diseases including rheumatoid arthritis and cancer. Importantly, high levels of MMPs often correlated with poor prognosis in human patients (reviewed in REF. 5 ). However, recent clinical data indicate that the relationship between § These authors contributed equally to this paper. Competing interests statementThe authors declare no competing financial interests. DATABASESThe following terms in this article are linked online to: Entrez Genome: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene DmMmp1 | DmMmp2 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMMPs and disease is not simple; for example, increased MMP activity can enhance tumour progression or can inhibit it (reviewed in REF. 6 ). This complex relationship between MMP expression and cancer has increased the basic and clinical interest in understanding MMP function in vivo, but it has also focused attention on MMPs and pathology, and relatively less attention has been focused on the normal roles of these enzymes. MMP proteolysisMMPs are members of the metzincin group of proteases, which are named after the zinc ion and the conserved Met residue at the active site 11,12 . Recent work has generated a unified peptidase nomenclature 13 Functions of MMP proteolysisHistorically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. However, MMP proteolysis can create space for cells to migrate, can produce specific substrate-cleavage fragments with independent biological activity, can MMPs in bone modelling and remodellingBone is an important site of ongoing tissue remodelling during development...

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“…This topic has been reviewed recently 81 , but here we will discuss a few of the most important findings.…”

Section: Mmps In Inflammation and Woundingmentioning

confidence: 99%

Matrix metalloproteinases and the regulation of tissue remodelling

Page-McCaw

Ewald

Werb

2007

Nat Rev Mol Cell Biol

2,589

2,180

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“…The key shortcoming of the MMP inhibitor trials is that these drugs lack specificity (Coussens et al, 2002;Parks et al, 2004). Not only do they block the activity of all 24 MMPs, these compounds also inhibit the activity of the related ADAM and ADAMTS proteinases as well as other metalloenzymes.…”

Section: Significancementioning

confidence: 99%

“…Despite the largely disappointing clinical trials, several studies in mice and cell models have convincingly demonstrated that specific MMPs are indeed essential mediators of tumor progression and invasion (Coussens et al, 2002;Hotary et al, 2003;Hotary et al, 2002;Wilson et al, 1997). In a complex tissue environment, like cancer, several cell types (resident, inflammatory, tumor) express several, different MMPs, and these proteinase can either promote or restrain disease or repair processes by affecting multiple and apparently opposing processes by the same cell at the same time (Coussens et al, 2002;Egeblad and Werb, 2002;Parks et al, 2004). For example, we have determined that epithelial MMP-7 is required for wound closure and generation of antimicrobial activity (Dunsmore et al, 1998;Wilson et al, 1999) (clearly beneficial functions), but it also promotes neutrophil activation, which can be damaging and lethal McGuire et al, 2003).…”

Section: Significancementioning

confidence: 99%

Control of matrix metalloproteinase catalytic activity

2007

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SummaryAs their name implies, MMPs were first described as proteases that degrade extracellular matrix proteins, such as collagens, elastin, proteoglycans, and laminins. However, studies of MMP function in vivo have revealed that these proteinases act on a variety of extracellular protein substrates, often to activate latent forms of effector proteins, such as antimicrobial peptides and cytokines, or to alter protein function, such as shedding of cell-surface proteins. Because their substrates are diverse, MMPs are involved in variety of homeostatic functions, such as bone remodeling, wound healing, and several aspects of immunity. However, MMPs are also involved in a number of pathological processes, such as tumor progression, fibrosis, chronic inflammation, tissue destruction, and more. A key step in regulating MMP proteolysis is the conversion of the zymogen into an active proteinase. Several proMMPs are activated in the secretion pathway by furin proprotein convertases, but for most the activation mechanisms are largely not known. In this review, we discuss both authentic and potential mechanisms of proMMP activation.

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“…Moreover, the airway epithelium also generates airway mucins that facilitate mucociliary clearance of inhaled particulates or microorganisms (103,104). Recent studies suggest that DUOX may participate in these responses as well, as illustrated by DUOX1-mediated production of epithelial mucins, such as MUC1 and MUC5AC, in response to inflammatory mediators such as neutrophil elastase or tumor necrosis factor (TNF)-α (105,106).…”

Section: Functions Of Epithelial Duox: Host Defense and Intracellularmentioning

confidence: 99%

“…4. Critical to the activation of these signaling pathways is the proteolytic cleavage of membrane-associated EGFR ligands by cell surface proteases, such as TNFα-converting enzyme (TACE; ADAM17), a member of the a disintegrin and metalloproteinase (ADAM) family of metzincin metalloproteinases (105,108,121), and matrix metalloproteinases (MMPs) such as gelatinase B (MMP-9), which play critical roles in epithelial host defense and in epithelial repair in response to injury (104,122,123). An important common structural and functional feature shared by the ADAM/MMP proteases is the presence of an invariant cysteine-containing pro-domain, which maintains latency by ligating the active site Zn 2+ , and is susceptible to oxidative disruption (124)(125)(126)(127).…”

Section: Functions Of Epithelial Duox: Host Defense and Intracellularmentioning

confidence: 99%

NADPH oxidases in lung biology and pathology: Host defense enzymes, and more

Vliet

2008

Free Radical Biology and Medicine

187

192

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The deliberate production of reactive oxygen species (ROS) by phagocyte NADPH oxidase is widely appreciated as a critical component of antimicrobial host defense. Recently, additional homologs of NADPH oxidase (NOX) have been discovered throughout the animal and plant kingdoms, which appear to possess diverse functions in addition to host defense, including cell proliferation, differentiation, and regulation of gene expression. Several of these NOX homologs are also expressed within the respiratory tract, where they participate in innate host defense as well as in epithelial and inflammatory cell signaling and gene expression, and fibroblast and smooth muscle cell proliferation, in response to bacterial or viral infection and environmental stress. Inappropriate expression or activation of NOX/DUOX during various lung pathologies suggests their specific involvement in respiratory disease. This review summarizes the current state of knowledge regarding the general functional properties of mammalian NOX enzymes, and their specific importance in respiratory tract physiology and pathology.

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Matrix metalloproteinases as modulators of inflammation and innate immunity

Cited by 1,706 publications

References 140 publications

Matrix metalloproteinases and the regulation of tissue remodelling

Matrix metalloproteinases and the regulation of tissue remodelling

Control of matrix metalloproteinase catalytic activity

NADPH oxidases in lung biology and pathology: Host defense enzymes, and more

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