• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Pathol Int. Author manuscript; available in PMC Aug 17, 2013.
Published in final edited form as:
PMCID: PMC3745773
NIHMSID: NIHMS492993

Matrix metalloproteinases, a disintegrin and metalloproteinases, and a disintegrin and metalloproteinases with thrombospondin motifs in non-neoplastic diseases

Abstract

Cellular functions within tissues are strictly regulated by the tissue microenvironment which comprises extracellular matrix and extracellular matrix-deposited factors such as growth factors, cytokines and chemokines. These molecules are metabolized by matrix metalloproteinases (MMP), a disintegrin and metalloproteinases (ADAM) and ADAM with thrombospondin motifs (ADAMTS), which are members of the metzincin superfamily. They function in various pathological conditions of both neoplastic and non-neoplastic diseases by digesting different substrates under the control of tissue inhibitors of metalloproteinases (TIMP) and reversion-inducing, cysteine-rich protein with Kazal motifs (RECK). In neoplastic diseases MMP play a central role in cancer cell invasion and metastases, and ADAM are also important to cancer cell proliferation and progression through the metabolism of growth factors and their receptors. Numerous papers have described the involvement of these metalloproteinases in non-neoplastic diseases in nearly every organ. In contrast to the numerous review articles on their roles in cancer cell proliferation and progression, there are very few articles discussing non-neoplastic diseases. This review therefore will focus on the properties of MMP, ADAM and ADAMTS and their implications for non-neoplastic diseases of the cardiovascular system, respiratory system, central nervous system, digestive system, renal system, wound healing and infection, and joints and muscular system.

Keywords: ADAM, ADAMTS, extracellular matrix, matrix metalloproteinase, non-neoplastic diseases, tissue inhibitor of metalloproteinases

Matrix metalloproteinases (MMP), a disintegrin and metalloproteinases (ADAM) and ADAM with thrombospondin motifs (ADAMTS) are members of the metzincins superfamily of zinc-based proteinases. Previous biochemical studies have indicated that these metalloproteinases are capable of digesting extracellular matrix (ECM) macromolecules and non-ECM molecules including receptors, growth factors, cytokines and chemokines, all of which are determinants of the tissue microenvironment. Studies on human diseased tissues and experimental analyses using genetic engineering techniques have demonstrated the expression and function of these proteinases in various tissues. Accordingly, these proteinases are considered to play a central role as regulators of the tissue microenvironment under physiological conditions during development and tissue remodeling and under pathological conditions contributing to tissue destruction. In cancer tissues, these proteinases, especially MMP and ADAM, are implicated in cancer cell proliferation and progression, and several review articles on the roles of MMP and ADAM in cancer have been published.14 In this article therefore we review the biochemical characteristics of MMP, ADAM and ADAMTS and the regulation of activities by tissue inhibitors of metalloproteinases (TIMP) and reversion-inducing, cysteine-rich protein with Kazal motifs (RECK). This review will provide up-to-date information about the expression and function of these proteinases in non-neoplastic diseases. Since the substrates of MMP, ADAM and ADAMTS are ubiquitously distributed in all organs of the body, they are potentially involved in almost all non-neoplastic diseases. Due to page limitations, however, we will focus on the diseases of the cardiovascular system, respiratory system, central nervous system, digestive system, renal system, wound healing and infection, and joints and muscular system.

STRUCTURES AND CHARACTERISTICS OF MMP, ADAM, ADAMTS AND THEIR INHIBITORS

MMP (matrix metalloproteinases)

MMP are a family of proteinases composed of 23 members in humans. Based on their structural characteristics, they are classified into secreted-type MMP and membrane-anchored MMP; both types are divided into subgroups according mainly to the domain structures and substrate specificity (Fig. 1 and Table 1). MMP can digest at least one ECM macromolecule, but accumulated lines of evidence demonstrate that most MMP also cleave non-ECM molecules such as growth factors, cytokines and their receptors (Table 1). The molecular structure of an MMP generally consists of four functional domains. A signal peptide for secretion is followed by a propeptide, of around 10 kDa, which contains a conserved cysteine switch motif. The catalytic domain, of around 20 kDa, has a conserved motif binding a zinc ion involved in proteolysis. In the latent MMP (proMMP), the zinc ion is linked to a sulfhydryl of the cysteine switch. The C-terminal hemopexin-like domain, of around 30 kDa, consists of four blades stabilized by a disulfide bond, and mediates substrate and inhibitor interactions. A small hinge region separates the catalytic domain from the hemopexin-like domain. Several MMP such as gelatinases and membrane-anchored MMP possess additional domains and some MMP (matrilysins) lack the hemopexin-like domain, as illustrated in Figure 1.

Figure 1
Domain structures of matrix metalloproteinases (MMP), a disintegrin and metalloproteinases (ADAM), and a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTS). MMP are classified into two categories, secreted-type MMP and membrane-anchored ...
Table 1
Substrates of human matrix metalloproteinases

Collagenases (MMP-1, MMP-8 and MMP-13) can digest major fibrillar collagens in their triple-helical domain at physiological pH. Gelatinases (MMP-2 and MMP-9) have additional collagen-binding type II repeats of fibronectin, and they efficiently cleave denatured collagens (gelatins). MMP-2 degrades type IV, V, VII, X and XI collagens, elastin, fibronectin, laminin and non-ECM molecules. MMP-9 degrades type III, IV and V collagens, N-telopeptides of type I collagen, aggrecan, cartilage link protein and elastin (Table 1). MMP-9 also activates cytokines and transforming growth factor-β (TGF-β), and converts plasminogen into angiostatin. Stromelysins (MMP-3 and MMP-10) digest a wide array of substrates, including aggrecan, fibronectin, nidogen, laminin, type IV, IX and X collagens, tenascin, vitronectin and decorin. Matrilysins (MMP-7 and MMP-26) lack the hinge region and hemopexin-like domain. Substrates of MMP-7 include aggrecan, fibronectin, type IV collagen, laminin and entactin. MMP-26 degrades type IV collagen, fibronectin, vitronectin and fibrinogen, and activates proMMP-9. Furin-activated MMP (MMP-11 and MMP-28) have an RKRR sequence (furin-recognition site) at the end of the propeptide domain and thus they are activated intracellularly by the action of furin and other proprotein convertases. MMP-11 has only weak proteolytic activity against gelatin, laminin, fibronectin and aggrecan, but also digests α1-proteinase inhibitor, α2-macroglobulin and insulin-like growth factor binding protein-1 (IGFBP-1). MMP-28 has activity against casein, but natural substrates are not known. Other secreted-type MMP (MMP-12, MMP-19, MMP-20, MMP-21 and MMP-27) diverge in sequence and substrate specificity compared to the previous groups. Macrophages are a major source of MMP-12 (metalloelastase), an enzyme that can degrade elastin, aggrecan, fibronectin, laminin and type IV collagen.

The membrane-anchored MMP are major mediators of pericellular proteolysis, modulating proliferation, apoptosis, differentiation and migration.5,6 The group of membrane-type MMP (MT-MMP) includes four type I transmembrane enzymes (MMP-14, MMP-15, MMP-16 and MMP-24) and two glycosylphosphatidylinositol-anchored proteases (MMP-17 and MMP-25) (Table 1). All MT-MMP have a furin cleavage motif at the end of the propeptide. With the exception of MMP-17 and MMP-23, the membrane-anchored MMP are capable of activating proMMP-2 (Table 1). Importantly, MMP-14 has collagenase activity.7 MMP-23 (cysteine array-MMP, MIFR) is a type 2 transmembrane-type MMP and digests gelatin, but information about other substrates is limited (Table 1).

Expression of most MMP is tightly regulated at the transcriptional level by hormones, growth factors, cytokines, cell-cell interactions, cell-ECM interactions and transformation.8 Activation of proMMP necessitates the disruption of the interaction between the conserved cysteine in the prodomain and the zinc from the catalytic site. During extracellular activation, removal of the prodomain can occur through proteolytic cleavage, and plasmin is believed to be an important in vivo activator for some MMP such as MMP-3.9 Several MMP are intracellularly activated in the Golgi by furin-like proteinases and pericellular activation of proMMP-2 by MT-MMP has also been demonstrated.5,6,8

ADAM (a disintegrin and metalloproteinases)

Thirty-eight members of the ADAM family have been cloned in various species (http://people.virginia.edu/~jw7g/Table_of_the_ADAMs.html). However, the human genome contains only 25 ADAM genes including ADAM-like decysin 1 (ADAMDEC1), and four are pseudogenes.10 Among them, 13 ADAM exhibit proteinase activity (proteolytic ADAM) and the other eight ADAM are non-proteolytic ADAM (Table 2). The structure of their NH2-terminal domains is similar to the corresponding domains of MMP and MT-MMP (Fig. 1). The metalloproteinase domain is followed by a disintegrin domain and a cysteine-rich domain. The disintegrin domain has a structure resembling fibronectin, including RGD sequences forming a stretch called the disintegrin-loop. This site was originally reported to act as the binding site to integrin receptors,11 but a recent study on the crystal structure has demonstrated that the disintegrin and cysteine-rich domains form a C-shaped structure, suggesting that the disintegrin-loop is packed by the cysteine-rich domain and inaccessible for protein binding.12 On the other hand, the cysteine-rich domain possesses the hypervariable region, which is thought to be responsible for the specificity of protein interactions. ADAM also possess an epidermal growth factor-like domain, a transmembrane domain and a cytoplasmic domain. Some ADAM have an SH3-binding site in a cytoplasmic domain which can activate SH3-containing signaling molecules like Src and Grb.11 Several ADAM contain potential phosphorylation sites for serine-threonine and/or tyrosine kinases.11 ADAM such as ADAM9, ADAM11, ADAM12 and ADAM28 have isoforms that lack their transmembrane and cytoplasmic domains, forming the secreted ADAM proteins (Table 2). ADAM15 and ADAM22 also have splice variants, which affect the exons encoding the cytoplasmic domain, and ADAM19 has a short isoform that lacks the propeptide, metalloproteinase and disintegrin domains. Proteolytic ADAM contain the consensus sequence of amino acids ‘HEXXHXXGXXH’ necessary to hold the Zn2+ and an invariant ‘Met turn’ in its metalloproteinase domain, which is the common structure of the metzincin family. The metalloproteinase domain of ADAMDEC1 contains a Zn2+-binding site replaced by an aspartic residue showing the sequence of ‘HELGHVLGMPD’, which is reflective of a proteolytic ADAM.10 Non-proteolytic ADAM are believed to play a role in cell attachment or in cell fusion through other domains such as the disintegrin domain.

Table 2
The human a disintegrin and metalloproteinase (ADAM) gene family

One of the major functions of proteolytic ADAM is ectodomain shedding of membrane proteins. ADAM17 has been most extensively examined and is known to release soluble tumor necrosis factor-α (TNF-α) from its membrane precursor, therefore this proteinase is called TNF-α converting enzyme (TACE). ADAM17 appears to also be responsible for shedding other membrane proteins including proTGF-α, pro-heparin binding epidermal growth factor (pro-HB-EGF), pro-amphiregulin and pro-epiregulin (Table 2).13 ADAM9 and ADAM12 are implicated in the shedding of pro-HB-EGF.14 Some membrane proteins such as Notch, CD44 and amyloid precursor protein are shed by ADAM and then subjected to regulated intramembrane proteolysis (RIPping) by γ-secretase, which is composed of the aspartate proteinases, presenilins 1 and 2. Since it is likely that ectodomain shedding by ADAM regulates the RIPping function of γ-secretase, modulation of RIPping is considered to be another function of ADAM.3,10 Like MMP, some ADAM can also degrade ECM substrates and IGFBPs: ADAM10 cleaves type IV collagen,15 ADAM12 digests gelatin, type IV collagen and fibronectin,16 ADAM15 cleaves type IV collagen and gelatin,17 and ADAM28 cleaves IGFBP-3.18 (Table 2).

ADAMTS (ADAM with thrombospondin motifs)

ADAMTS include 19 members, which do not have a transmembrane domain. Instead, they possess one or several thrombospondin-like motifs (Fig. 1). Cleavage of the thrombospondin-like motif19 (which is believed to be attached to the cell membrane20) regulates both the proteinase activity and the localization of the enzyme. ADAMTS1, 2, 3, 4, 5, 7, 8, 9, 14, 15, 16, 18 and 20 are ECM-degrading proteinases (Table 3).19,21,22 ADAMTS1, 4, 5, 8, 9, 15, 16, 18 and 20 are considered to cleave specific Glu-X bonds of the core protein of aggrecan, although the cleavage of aggrecan by ADAMTS20 has not been directly determined. Due to their aggrecan-degrading activity, ADAMTS4 and ADAMTS5 are called aggrecanase-1 and aggrecanase-2, respectively,23,24 and brevican and versican are also cleaved by these enzymes (Table 3).25,26 ADAMTS13 is a von Willebrand factor-cleaving protease, and its mutation causes thrombotic thrombocytopenic purpura.27

Table 3
The human a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTS) gene family

TIMP (tissue inhibitors of metalloproteinases) and RECK (reversion-inducing, cysteine-rich protein with Kazal motifs)

TIMP are the major physiological inhibitors of MMP, although α2-macroglobulin (an inhibitor of many classes of proteinases) can also inhibit MMP activity. Four homologous TIMP (TIMP-1, TIMP-2, TIMP-3 and TIMP-4), of 21 to 30 kDa, have been cloned in humans. All TIMP inhibit stoichiometrically the activities of MMP in a 1:1 molar ratio; however TIMP-1 can not efficiently inhibit MT-MMP. The activities of ADAM10, ADAM12, ADAM17, ADAM28 and ADAM33 are effectively inhibited by TIMP-3, although some inhibitory activity of TIMP-1, TIMP-2 and TIMP-4 to ADAM10, ADAM17, ADAM28 and/or ADAM33 has also been reported.10 On the other hand, ADAM8, ADAM9 and ADAM19 are not inhibited by any TIMP.10 Since the inhibitory activity of TIMP-3 against ADAM is similar to that of MMP, TIMP-3 may be a common inhibitor to the ADAM. However, it is not well known if, in addition to TIMP-3, other types of ADAM inhibitors exist. TIMP-3, but no other TIMP, is also an efficient inhibitor of ADAMTS4 and ADAMTS5.19 Besides the inhibitor activities, TIMP have other important biological functions such as influencing cell proliferation, apoptosis and angiogenesis and regulating the activation of proMMP-2 and proMMP-9 through their complex formation (proMMP-2/TIMP-2 and proMMP-9/TIMP-1 complexes).8,28 RECK is a glycosylphosphatidylinositol (GPI)-linked glycoprotein, which inhibits MMP-2, MMP-9, MT1-MMP (MMP-14) and also ADAM10.29,30 This inhibitor has been reported to inhibit angiogenesis in vivo probably by inhibiting MMP-2 activity.30 However, it is not known whether RECK has an inhibitory activity on other MMP and ADAM/ADAMTS.

INVOLVEMENT OF MMP, ADAM AND ADAMTS IN NON-NEOPLASTIC DISEASES

Diseases of the cardiovascular system

Remodeling of the myocardium

A number of studies have shown that MMP are involved in the remodeling of the myocardium in cardiac diseases including myocardial infarction, left ventricular hypertrophy and dilated cardiomyopathy.31 MMP-2 and MMP-9 are overexpressed in human myocardial infarction and dilated cardiomyopathy, and MMP-1, MMP-13 and MMP-14 are elevated during pressure overload hypertrophy.31 Using a transgenic mouse model expressing human MMP-1 in cardiomyocytes Kim et al. demonstrated that a direct disruption of the ECM of the heart results in loss of collagen and a deterioration of systolic and diastolic function, mimicking the progression of human heart failure.32 Heymans et al. showed that in an acute myocardial infarction model, cardiac rupture is partially protected in MMP-9 knockout mice,33 but not in wild-type, MMP-3 knockout or MMP-12 knockout mice. In addition, pharmacological inhibition or gene deletion of MMP-2 protects against cardiac rupture in mice, preventing ECM degradation and delaying the phagocytic removal of infarcted myocardium by macrophages.34 In particular, cleaved fragments of fibronectin and laminin generated by MMP-2 appear to be critical in the promotion of macrophage accumulation in the infarcted myocardium.34 Moreover, adenoviral overexpression of TIMP-1 after myocardial infarction delays infarct healing and completely protects mice against rupture.33 Therefore, the activity of MMP-2 and MMP-9 appears to be necessary for tissue repair following myocardial infarction and contributes to infarct rupture. Targeted deletion of MMP-9 is known to attenuate left ventricular dilation after experimental myocardial infarction in mice.35 MMP-9 deficient mice exhibit decreased collagen and a reduced number of macrophages in the infarcted tissue compared to wild-type animals, suggesting that MMP-9 plays a prominent role in ECM remodeling after myocardial infarction.35 Collectively, these studies suggest that MMP-2 and MMP-9 are possible targets for treatment of myocardial infarction and subsequent remodeling.

Atherosclerosis

The primary cause of heart disease in the Western world is atherosclerosis, an inflammatory process that affects the vessel wall of large and medium-sized arteries. Genetic and environmental factors associated with this disease include elevated low-density lipoprotein and very low-density lipoprotein, obesity, diabetes, high blood pressure, a high-fat diet and smoking.36 The acute coronary syndrome, including myocardial infarction and stroke, results from an erosion or rupture of the fibrous cap surrounding the luminal side of the atherosclerotic lesion, leading to thrombus formation.37 Henney et al. first demonstrated MMP-3 expression in human atheroma, but not in normal vessels.38 Other MMP such as MMP-1, MMP-2 and MMP-9 were subsequently detected in the macrophages, smooth muscle cells and endothelial cells of the atheroma.39 These MMP were believed to be ultimately responsible for plaque destabilization and rupture.40,41

Studies using genetically modified mice, however, have revealed a more complex role of MMP in atherosclerosis. Apolipoprotein-E (Apoe) deficient mice develop atherosclerotic lesions similar to those observed in humans, although they do not spontaneously rupture or erode.42 Transgenic overexpression of human MMP-1 in macrophages of Apoe knockout mice surprisingly resulted in less advanced atherosclerosis, suggesting that MMP-1 has a protective role in human atherosclerosis, probably through tissue repair (Fig. 2).43 Studies have indicated that MMP-3 may also be athero-protective.4446 On the other hand, several MMP appear to contribute to the development and severity of plaque. Transgenic rabbits expressing human MMP-12 in macrophages47 showed increased fatty streaks, and loss of MMP-2 or MMP-12 in Apoe knockout mice resulted in smaller aortic lesions,45,48 indicating a detrimental role of these two MMP in atherosclerosis. Deficiency of MMP-8 in Apoe-null mice resulted in smaller lesions with increased collagen deposition,49 and absence of MMP-13 led to thinner and less aligned collagen fibers in the plaque.50 Lesions of low-density lipoprotein receptor-deficient mice engrafted with MMP-14 knockout bone marrow contained more interstitial collagen than those receiving wild-type bone marrow.51 Together, these studies indicate that collagenolytic MMP (MMP-8, MMP-13, and MMP-14) all contribute to collagen remodeling in the atherosclerotic lesion. A sequence variant of the human MMP-9 promoter, leading to increased expression of the enzyme, has been associated with more severe atherosclerosis,52 but the precise role of MMP-9 in this disease remains unclear. Several studies using knockout53 and transgenic mice,54,55 indicate that MMP-9 may contribute to plaque growth and destabilization, leading to thrombus formation.56 However, other studies suggest that MMP-9 could rather play a protective and pro-fibrotic role in atherosclerosis.57,58

Figure 2
Role of matrix metalloproteinases (MMP) in atherosclerosis and aneurysm formation. Studies using Apolipoprotein-E (Apoe) knockout mice have demonstrated that MMP expressed in the atheroma are present mainly in macrophages but also in other cells critical ...

ADAM could also have important functions in atherosclerosis, although this is less studied than MMP. ADAM9 and ADAM15 have been detected in the human atheroma,59 and increased expression of ADAM17 has been associated with smaller lesions in mice,60 suggesting a protective role of this proteinase in atherosclerosis. Studies also indicate that ADAMTS1 and ADAMTS7 contribute to smooth muscle cell migration into the neointima.61,62 However, data detailing the role of ADAM and ADAMTS in atherosclerosis are still limited.

Aneurysm

MMP have been detected in human abdominal aortic aneurysms, which are lesions with the potential to rupture.63,64 MMP overexpressed in human aneurysm include MMP-1,65 MMP-2,66,67 MMP-3,65,68 MMP-9,66,69,70 MMP-12,71 MMP-1372 and MMP-14.73 Elevated MMP-8 and MMP-9 were present more in ruptured aneurysms than in non-ruptured ones, suggesting a role of both proteinases in this lethal complication (Fig. 2).74 Several experimental animal models of aortic aneurysm have been developed, including angiotensin II infusion, periaortic application of CaCl2 and elastase perfusion.75 These models have provided strong evidence that MMP occupy a central function in aneurysm formation. In particular, absence of either MMP-2 or MMP-9 protected mice from experimental abdominal aortic aneurysm.76,77 It has been also suggested that plasminogen regulates macrophage activation of proMMP-9, leading to macrophage migration and medial degeneration.78 Deficiency of TIMP-1 resulted in larger experimental thoracic aortic aneurysms,79 but mice deficient in TIMP-2 developed smaller aneurysms, probably a secondary result of impaired activation of proMMP-2 in the absence of TIMP-2.80 Transplantation with bone marrow from MMP-14 (MT1-MMP) null mice resulted in a resistance to aortic aneurysm formation.81 These findings support the importance of MT1-MMP/TIMP-2-driven proMMP-2 activation in aneurysm formation (Fig. 2).

A small number of microaneurysms can also form spontaneously in the aorta of Apoe deficient mice. These microaneurysms, located under advanced atherosclerotic lesions, result from an invasion of lesion macrophages into the underlying disrupted media. Studies have demonstrated that this invasive process necessitates MMP activity. Carmeliet et al. first observed that absence of a urokinase-type activator of plasminogen resulted in resistance to microaneurysm formation due to a lack of plasmin-activated MMP in the plaque.9 Deficiency in either MMP-3,44 MMP-953 or MMP-1253 in Apoe knockout mice resulted in decreased medial degradation, and in TIMP-1 knockout mice, an augmented number of microaneurysms was observed together with elevated MMP activity.82,83 Over the years, animal models have therefore clearly demonstrated that MMP play a key and concerted role in aneurysm formation (Fig. 2).

Diseases of the respiratory system

Emphysema/chronic obstructive pulmonary disease

The understanding of the pathogenesis of emphysema in patients deficient in α1-antitrypsin provided the initial idea that a proteinase/antiproteinase imbalance was responsible for the disease.84 Since neutrophil elastase is inhibited by α1-antitrypsin, excess elastase activity was thought to be responsible for the destruction of the lung leading to emphysema. However, the development of emphysema in MMP-1 transgenic mice expanded the original concept of a trypsin/antitrypsin imbalance to a proteinase/antiproteinase imbalance theory.85 Indeed, bronchoalveolar lavage (BAL) fluid from patients with emphysema contains more MMP-1 compared to fluid from healthy volunteers, and this is associated with increased secretion of active MMP-1.86 Moreover, immunohistochemistry on emphysematous lung tissue has shown that MMP-1 is expressed in epithelial cells, especially type II pneumocytes. Increased MMP-1 expression in the epithelial cells of smokers may result from a prolonged activation of the ERK mitogen-activated protein kinase pathway.87 These data suggest that inflammatory cells may not be exclusively responsible for lung tissue destruction, but that MMP-1 expression in epithelial cells can cause emphysema (Fig. 3).88 MMP-12 knockout mice have been reported to exhibit resistance to cigarette smoke-induced emphysema, which was believed to be attributed to a diminished metalloelastase activity. However, a recent study demonstrated that MMP-12 is involved in inflammatory regulation in this model.89 The spectrum of MMP in human diseases differs from animal models including mice and guinea pigs. In fact, no increase in MMP-12 expression or activity was found in human emphysema.90 A recent study in patients identified a polymorphism within the MMP-12 promoter correlating with lung functions.91 Therefore, the data are conflicting and it could be possible that MMP-12 is essential to cigarette smoke-induced emphysema in mice, but may not be equally critical in humans. MMP-9 is secreted mainly from neutrophils in response to inflammatory stimuli including interleukin (IL)-17 produced by lymphocytes.90,92,93 A recent study in transgenic mice demonstrated that mice chronically expressing increased MMP-9 eventually develop lung destruction similar to that of emphysema.94 It is very likely that multiple MMP secreted from inflammatory cells and epithelial cells contribute to the complex pathological condition seen in emphysema/chronic obstructive lung disease (Fig. 3).95 There is relatively little evidence for a link between ADAM/ADAMTS and emphysema. However, polymorphisms in the ADAM33 gene have been shown to be related to an accelerated decline in forced expiratory volume in 1 second (FEV1),96,97 airway hyperresponsiveness and airway inflammation and this protein is believed to be critical in asthma pathogenesis.98

Figure 3
Role of matrix metalloproteinases (MMP) in emphysema and acute respiratory distress syndrome (ARDS). In patients with emphysema (left panel), MMP-1 is expressed in epithelial cells, especially type II pneumocytes stimulated by cigarette smoke. MMP-12 ...

Acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is caused by an increase in the permeability of the alveolar-capillary barrier and the subsequent impairment of gas-exchange resulting from various systemic insults such as sepsis. Chronically, the disease can progress to fibrotic lung injury.99 Since the alveolar basement membrane is primarily composed of type IV collagen, MMP are likely to be involved in the extensive ECM remodeling that occurs in ARDS. In the acute phase of ARDS, increased MMP-2, 8, 9 and TIMP1 levels in BAL fluid are found due to a general inflammatory reaction including the upregulation of cytokines.100,101 Lung tissue remodeling can then be exacerbated by O2 administration during treatment, since hyperoxia has been shown to upregulate collagenase and gelatinase activity.102 The complexity of the events in early ARDS is highlighted by the observation that not only the proteinase levels, but also markers of collagen synthesis, are increased.103,104 The response to the initial insult may therefore drive both destruction and synthesis of ECM and, in some cases, ultimately result in fibrosis.

The functional importance of MMP activity in ARDS has been investigated in animal models of acute lung injury. In an immune complex deposition model, mice deficient in MMP-3, MMP-9 or MMP-12 had less severe lung injury than wild-type mice.105,106 Neutralization of TIMP-2 exacerbated lung damage in this model.107 Mice deficient in TIMP-3 also developed more severe lung injury in a model of sepsis which was associated with reduced collagen and fibronectin levels.108 In a cardiopulmonary bypass model inhibition of MMP and neutrophil elastase activity by a chemically modified tetracycline reduced lung injury.109 Similar protective effects by MMP inhibition have been demonstrated in animal models of sepsis.110,111 Although a comparison of the various studies is difficult due to the diverse models and different MMP examined, these data indicate that MMP contribute to the initial lung insult in ARDS and suggest that MMP inhibition may be protective in acute lung injury (Fig. 3). However, modulation of MMP activity should be sufficiently early in the course of the disease in order to halt the pathological cascade initiated by excessive proteinase activity.

Interstitial pulmonary fibrosis

The expression of many MMP (MMP-1, −2, −7, −9, −12 and −13) and all TIMP (TIMP-1, −2, −3 and −4) has been reported in patients with interstitial pulmonary fibrosis. Among them, MMP-7 appears to be the most important, since gene expression analysis of pulmonary fibrosis revealed the most significant change in MMP-7,112 and it was not only overexpressed but also activated in the lungs of patients.113 In addition, an animal model of fibrosis was protected from disease when MMP-7 was knocked out.112 Other MMP and TIMP are mainly expressed in inflammatory cells and myofibroblasts of the fibrotic tissue and it is likely they are not specific to the disease. In addition, the active forms of these MMP have not been demonstrated. The role of ADAM/ADAMTS in interstitial pulmonary fibrosis has not yet been clarified. However, microarray analysis of TGF-β-treated lung cells revealed upregulation of ADAM19 and ADAMTS9, which can promote the production of collagen.114

Bronchial asthma

BAL fluid and sputum of patients with bronchial asthma exhibit an increase in MMP-9.115 The main source of MMP-9 is thought to be neutrophils and eosinophils. In addition, MMP-1116 and MMP-2117 have been shown to be upregulated in patients’ sputum. Various cytokines including IL-1, IL-4, IL-5, IL-9, IL-13, monocyte chemoattractant protein-1 and TGF-β have been shown to regulate MMP in asthma.118 ADAM8 and ADAM33 are upregulated in bronchial asthma patients and their expression correlates with the severity of the disease. Expression of these ADAM is promoted by TH2 cytokines and they are believed to play an important role in the recruitment of leukocytes. Linkage analysis in 260 families led to identification of a region on chromosome 20p13 containing an asthma susceptibility gene,119 and subsequent positional cloning identified ADAM33 as the candidate gene. In addition, a large number of case-control and family-based association studies focusing on ADAM33 confirmed the original finding.

Tuberculosis

MMP are potentially involved in the lung tissue destruction process in tuberculosis. Upregulation of MMP-9 mRNA is observed in cells isolated from the BAL fluid of patients with active tuberculosis and MMP-9 levels in the blood correlate with the severity of the disease.120,121 However, MMP-9 is probably not sufficient to degrade the lung structure because of its substrate specificities. Elkington et al. have shown that MMP-1 and MMP-7 are the most highly upregulated MMP in tuberculosis.122 These two MMP can degrade the major lung ECM components such as type I collagen and elastin. MMP-1 expression in epithelial cells in culture is driven by a monocyte-dependent network. Mycobacterium tuberculosis therefore drives a matrix degrading phenotype by both a direct infection of macrophages and an intercellular network that increases MMP secretion by epithelial cells.

Diseases of the central nervous system

Neuroinflammatory diseases

One of the characteristics of the central nervous system (CNS) is that the ECM is composed mainly of proteoglycans but no fibril-forming interstitial collagens. This uniqueness of the CNS ECM may result in a different process of tissue destruction by MMP. Although the expression of MMP in the normal adult brain is very low, several MMP are upregulated in the brain in response to injury. In neuroinflammatory diseases such as multiple sclerosis, human immunodeficiency virus (HIV) encephalitis and spinal cord injury, the disruption of the blood-brain barrier (BBB) by MMP, especially MMP-9, is considered to be central to the pathogenesis of these diseases.123

(a) Multiple sclerosis

In multiple sclerosis activated and antigen-specific T-cells, dendritic cells and monocyte/macrophages cross the BBB to enter the CNS. Within the CNS, these cells are reactivated and cooperate with resident astrocytes and microglia to migrate through the parenchyma and orchestrate myelin and axonal destruction, leading to severe destruction of normal CNS constituents. Among the MMP, MMP-9 has been shown to be important in the disruption and degradation of the brain ECM.123

(b) HIV encephalitis

HIV-infected macrophages enter the CNS early in the course of infection and around 20% of individuals develop HIV encephalitis, while 15% develop HIV-associated dementia in the United States.124 In addition, a new variant of HIV encephalitis called severe leukoencephalopathy has emerged from the development of recent antiretroviral therapy.125 In these diseases, a significant perivascular infiltration of macrophages and lymphocytes, astrogliosis, myelin loss and deterioration of neocortex including neuronal/axonal loss have been observed. HIV-infected human leukocytes exhibit increased expression of MMP-2 and MMP-9, which are believed to be important for transmigration across the BBB.126 In addition, CNS resident cells are known to exhibit high MMP levels in HIV encephalitis.127

(c) Spinal cord injury

Trauma resulting in spinal cord injury is the leading cause of permanent disability in young adults. Typically, immediately after spinal cord injury, inflammatory cells expressing various MMP invade the area of injury. Among them MMP-9128 and MMP-12129 are strongly upregulated during the acute period of injury. In an animal model either pharmacological blockade of MMP by inhibitor or targeted deletion of MMP-2 and MMP-9 in mice resulted in significant improvement of the damage.128

Neurodegenerative diseases

Several MMP and ADAM may be directly or indirectly involved in the pathogenesis of neurodegenerative diseases such as vascular cognitive impairment, Alzheimer’s disease and Parkinson’s disease.130

(a) Vascular cognitive impairment

In vascular cognitive disease, MMP are induced by hypoxic hypoperfusion of the white matter. Patients with this disease present with a high cerebrospinal fluid concentration of MMP-9.131 Induced MMP have been shown to increase the vascular permeability of the BBB. The disruption of the BBB then results in the activation of microglia and the recruitment of macrophages that can contribute to the tissue injury. Some MMP including MMP-2, MMP-3 and MMP-9 can break down myelin basic protein in brain tissue, and this may explain the demyelination commonly observed in the diseased brain due to vascular cognitive impairment.130

(b) Alzheimer’s disease

The pathological features of Alzheimer’s disease include neuronal tangles and amyloid plaques. Amyloid precursor protein (APP) is a transmembrane protein which functions in normal physiology. Secretases clip APP and the sites of cleavage determine the fate of the protein fragments. Several metalloproteinases such as MMP-2, ADAM9, ADAM10 and ADAM17 are reported to have α-secretase activity, which is involved in the degradation pathway of the APP turnover.132 Other proteinases, classified as β-secretase and γ-secretases, act together to produce amyloid-β peptide (Aβ), which is the principal proteinaceous component of amyloid plaques in Alzheimer’s disease. MMP may participate in the formation and clearance of Aβ in Alzheimer’s disease. Aβ can endogenously induce MMP in blood vessels, astrocytes and microglia. However, despite MMP production, no active form of MMP-9 is detected in patients with Alzheimer’s disease.133 The expression of ADAM10 in neurons is also reduced in Alzheimer’s diseased brains compared to controls.134 This suggests the possibility that disturbance of the clearance system involving MMP in the brain is related to the pathogenesis of Alzheimer’s disease.

(c) Parkinson’s disease

There is emerging evidence that MMP-3 plays an important role in the death of dopaminergic neurons. In vitro, apoptotic dopaminergic neurons release MMP-3, which acts as a mediator to activate microglia.135 The activated microglia releases TNF-α which leads to neuronal death. Also, a direct mechanism of active MMP-3 interacting with caspase-3 has been reported potentially leading to increased apoptosis of the neurons.136

Diseases in the digestive system focusing on liver and pancreas

Liver fibrosis

Liver fibrosis develops as a result of chronic liver wound repair following diverse insults. The ultimate outcome of liver fibrosis is the formation of hepatocyte nodules encapsulated by a fibrillar scar matrix. In the liver, hepatic stellate cells and Kupffer cells are thought to be the main source of MMP.137 Although there is minimal expression of MMP under physiological conditions, MMP-2 and MMP-9 are produced under inflammatory conditions. Hepatocytes produce MMP-13 upon injury and loss of MMP-13 has lead to attenuation of fibrosis in a mouse model of liver disease.138 In addition, infiltrated neutrophils produce MMP-8, another collagenolytic enzyme, which can contribute to the remodeling process. In liver fibrosis, hepatic stellate cells are converted to myofibroblastic cells and produce fibrillar collagens in the space of Disse. Prior to deposition, the normal ECM in the space of Disse, which is rich in basement membrane-like matrices, is proteolytically degraded by MMP-2 and MMP-9. A recent study showed that ADAM28 is overexpressed, probably by hepatic stellate cells, in the liver tissue from patients with chronic liver diseases and its expression levels correlate with the degree of liver fibrosis.139 However, no information is available on the consequences of ADAM28 expression in liver diseases.

Liver reperfusion injury

Reperfusion injury of the liver is believed to share similar mechanisms as seen in the brain, heart and lungs with regard to MMP.140 Stimuli induced by cytokines and reactive oxygen species due to ischemic-reperfusion injury cause a release of MMP-2 and MMP-9 from Kupffer cells and MMP-8 from infiltrated neutrophils. These enzymes act as inducers of cell apoptosis and ECM remodeling.

Acute pancreatitis

A limited number of articles on non-cancerous diseases of the pancreas have been published. It has been shown that MMP-9 levels in blood samples correlate with the severity of acute pancreatitis.141 Since neutrophils are the major source of MMP-9, it may reflect a neutrophilic inflammatory response in the pancreas.

Renal diseases

Acute kidney injury

Upregulation of MMP-2 and MMP-9 is found in acute kidney injury. MMP-2 and MMP-9 are implicated in the degradation of the tight junction protein zonula occludens-1 in the glomerulus,142 and MMP-9 is considered to contribute to the degradation of occludin in endothelial cells, resulting in increased vascular permeability.143 These data suggest that MMP mediate acute kidney injury and play a role in the changes of the vascular endothelium, glomeruli and tubular epithelial cells. Adhesion molecules have also been identified as critical targets of MMP in the kidney, consistent with the increased vascular and tubular permeability characteristic of acute kidney injury.142

Chronic kidney disease

The importance of MMP-2 and TIMP-1 in ECM remodeling during chronic kidney disease has been reported.144,145 It is suggested that an increase in ECM turnover soon after injury and reduced ECM degradation at later stages lead to interstitial fibrosis.142

Diabetic nephropathy

Diabetic nephropathy in animal models is associated with decreased expression of MMP-2 and MMP-9 in the kidneys.146,147 In humans, glomerular expression of MMP-2 is decreased and that of TIMP-2 is increased in patients with diabetic nephropathy compared to normal controls.148,149 TIMP-1 levels are also increased in serum and urine, showing a correlation of urinary TIMP-1 levels with increased urine albumin.150 Increased MMP inhibition and decreased MMP activity are consistent with augmented ECM deposition in diabetic nephropathy. Interestingly, increased MMP-9 in the plasma precedes the development of microalbuminuria in patients without changes in either MMP-1 or TIMP-1 levels.151 This finding is supported by recent data demonstrating that urinary levels of MMP-9 are elevated in type 2 diabetic patients, and correlate with albuminuria.152 Expression of MMP-24 (MT5-MP) is also known to correlate with tubular atrophy153 and polymorphisms in TIMP-3 are associated with diabetic nephropathy in type 1 diabetes,154 although the pathological meaning remains elusive.

Wound healing and infectious diseases

Wound healing

Wound tissues in humans and in experimental animals over-express multiple MMP including MMP-1, 2, 3, 8, 9, 10, 13, 14, 19 and 26. These MMP expectedly play a role in the complex process of wound healing that includes acute inflammatory reaction, regeneration of parenchyma cells, cell migration and proliferation, angiogenesis, contraction and tissue remodeling.155 During human skin wound healing, MMP-1 released by keratinocytes is critical for re-epithelialization by promoting cell migration through binding to integrin and type I collagen.156 In mouse wound healing, MMP-13 plays a key role in keratinocyte migration, angiogenesis through digestion of connective tissue growth factor and contraction by activation of latent TGF-β.157 Other MMP that may contribute to re-epithelialization include MMP-7, −9, −10 and −14, while MMP-3 might be involved in scar resorption.155

Infectious diseases

Accumulated evidence has suggested that MMP play a role in the immune response during bacterial infection. In periodontal inflammation, MMP are considered to not only contribute to tissue destruction but also to exert anti-inflammatory effects through the processing of cytokines. Mice deficient in MMP-3 exhibit delayed clearance of bacteria and impaired CD4+ T-lymphocyte migration during intestinal bacterial infection.158 Helicobacter pylori has been shown to induce MMP-1 expression in gastric epithelial cells, contributing to tissue destruction of the gastric mucosa.159 In macrophages, MMP-12 is intracellularly mobilized to phagolysosomes after the ingestion of bacteria and disrupts bacterial cellular membranes, leading to bacterial death. This antimicrobial activity of MMP-12 resides within the hemopexin-like domain.89

Diseases in joints and muscular system

Joint diseases

Excessive degradation of the cartilage ECM is a feature of two major joint diseases, osteoarthritis (OA) and rheumatoid arthritis (RA). In OA, the most common form of arthritis, increased production of proteinases by chondrocytes themselves leads to the breakdown of cartilage and little or no synovitis is present at least in the early stage of disease. On the other hand, RA, the most refractory and destructive form of arthritis, is characterized primarily by prominent and persistent synovitis and an expansion of inflammation, resulting in cartilage and bone destruction. Although all classes of proteinases are produced in these arthritides, MMP and ADAMTS are believed to be major players for the destruction of cartilage through degradation of ECM components, which are composed mainly of proteoglycans and collagens.8 In both arthritides, depletion of proteoglycans initially occurs and subsequently collagen fibrils are degraded, developing histological changes of fibrillation and laceration due to the destruction of the arcade structures of collagen fibrils in the cartilage.8 Accumulated lines of evidence have demonstrated that collagenolytic MMP (MMP-1, 8, 13 and 14) are responsible for the degradation of type II collagen (a major fibrillar collagen in the cartilage), whereas aggrecan (a major proteoglycan in the cartilage) is degraded by both aggrecanase-type ADAMTS (ADAMTS1, 4, 5, 8, 9, 15, 16, 18 and 20)8,19,22 and MMP (MMP-3, 7, 8, 9 and 13).8 The cleavage sites of the aggrecan core protein by MMP and ADAMTS are different and named as the MMP site (the Asn341–Phe342 bond) and the aggrecanase site (the Glu373–Ala374 bond).8,19

(a) OA

In human OA cartilage, MMP-1, 2, 3, 7, 8, 9, 13 and 14 are overexpressed by chondrocytes.8 Among these MMP, MMP-1, MMP-13 and MMP-14 (MT1-MMP) may play a direct role in collagen degradation because of their collagenolytic activity and common expression in the cartilage. MMP-14 potentially has a dual role in collagen degradation through both its collagenolytic activity and activation of proMMP-2 and proMMP-13. On the other hand, MMP-3 could be important to the cartilage destruction by activating proMMP-1, proMMP-7, proMMP-8, proMMP-9 and proMMP-13 and by digesting many ECM components such as aggrecan, type IX collagen and link protein.8 A recent study on human OA cartilage has suggested that proMMP-7 is activated through an interaction with CD151 and that MMP-7 is involved in chondrocyte cloning, a process of incomplete cartilage repair.160 The role of MMP in arthritis has also been examined using knockout and transgenic mouse models. Transgenic expression of active MMP-13 in mouse articular cartilage resulted in pathological changes similar to those observed in human OA, showing increased cleavage of type II collagen.161 However, in an OA model of MMP-3 deficient mice, accelerated cartilage destruction was greater compared to in wild-type mice.162 These changes were accompanied by increased aggrecanase and collagenase activity in the arthritic tissue of the MMP-3 knockout mice.162 Therefore, the functional role of MMP-3 in OA is not experimentally confirmed and the interaction of MMP is complex.

Among aggrecanase-type ADAMTS, ADAMTS4 (aggrecanase-1) and ADAMTS5 (aggrecanse-2) are considered to be major aggrecanases in OA. Mutation of the aggrecanase site of the aggrecan core protein in knock-in mice, conferring resistance to digestion by aggrecanases, resulted in diminished aggrecan loss and cartilage erosion in surgically induced OA.163 Thus, blocking aggrecanolysis in the aggrecan interglobular domain alone is chondroprotective.163 Recent studies on arthritis models using ADAMTS4 or ADAMTS5 knockout mice have demonstrated that deficiency of ADAMTS5, but not ADAMTS4, prevents aggrecan degradation and cartilage destruction,164,165 indicating that ADAMTS5 is an essential aggrecanase in mice. However, recent studies on human OA cartilage demonstrated that among ADAMTS1, 4, 5, 8, 9 and 15, ADAMTS4 is mainly overexpressed in OA cartilage, while ADAMTS5 expression is constitutive in OA and normal control cartilage.166 Moreover, the expression of ADAMTS4, but not ADAMTS5, is inducible or stimulated with IL-1 and TNF-α, major cytokines in OA.167 Thus, the differential role of ADAMTS4 and ADAMTS5 in human OA cartilage remains elusive.

Although overexpression of several ADAM in OA cartilage and chondrocytes has been reported, their function in joint diseases is not well understood. Based on the data obtained from ADAM15 knockout mice, ADAM15 is suspected to have a homeostatic rather than a destructive role in cartilage remodeling.168 Recently, it was reported that ADAM12 plays a role in chondrocyte proliferation by promoting the availability of insulin-like growth factor-I through cleavage of IGFBP-5 in human OA cartilage,169 suggesting the possible involvement of ADAM12 in cartilage repair.

(b) RA

The mechanism of articular cartilage destruction by proteinases is more complex in RA than OA, and composed of three pathways: destruction from the surface of the articular cartilage by proteinases present in the synovial fluid, destruction through direct contact of proteolytic synovium and/or pannus tissue to the articular cartilage and intrinsic destruction by proteinases derived from chondrocytes.8 Rheumatoid synovial tissue exhibits the overproduction of MMP-1, 2, 3, 8, 9 and 14 together with TIMP-1, 2 and 3.8 These MMP and TIMP, except for MMP-14 and TIMP-3, which are cell membrane-anchored and ECM-anchored, respectively, are secreted into the synovial fluid in the joint cavity, and accumulated MMP are believed to degrade the cartilage from the surface based on the imbalance between MMP and TIMP in favor of MMP.170 MMP-3 is detectable in serum samples from RA patients and is clinically used as a biomarker for diagnosis of RA, prognosis of joint destruction and monitoring of treatment for RA in Japan. Rheumatoid synovium is highly proteolytic, since it has gelatinolytic activity generated by the activation of proMMP-2 by MMP-14.171 Direct contact of this synovium may induce cartilage destruction at the peripheral portion of articular surface.171 Chondrocytes in RA also express MMP-1, 2, 3, 7, 9, 13, 14 (MT1-MMP), 16 (MT3-MMP) and ADAMTS4. All these proteinases may play a role in the ECM degradation within the cartilage. Rheumatoid synovium has been reported to overexpress ADAM15, ADAM17, ADAMTS4, ADAMTS5, ADAMTS7,172 and ADAMTS12,173 all believed to contribute to the disruption of the cartilage extracellular matrix. A role for ADAM15 in angiogenesis in the synovium has also been proposed.174

Muscular diseases

MMP and ADAM have been implicated in idiopathic inflammatory myopathies, where they are believed to participate in the disruption of the ECM, allowing infiltration of lymphocytes into the muscle tissue.175 Muscular dystrophies are characterized by a replacement of skeletal muscle by fat and connective tissue, and studies suggest that MMP-9 and ADAM12 contribute to the progression of these diseases.176,177

CONCLUSIONS

The main substrates of MMP and ADAMTS appear to be ECM macromolecules (Tables 1,,3),3), and almost all ECM components are efficiently digested when they act in conjunction with each other. Several cytokines, chemokines and growth factors are also metabolized by MMP and ADAM through a proteolytic activation and/or inactivation of these factors and their binding proteins and also through shedding and RIPping. In addition, some ADAM can modulate cell adhesion through binding to integrins and/or to other membrane receptors (Table 2). These direct effects of MMP, ADAM and ADAMTS induce cellular alterations including proliferation, differentiation, motility/migration, apoptosis and epithelial-mesenchymal transition (Fig. 4). Accordingly, timely and spatial expression of these metalloproteinases within the tissue is essential to biological phenomena of reproduction, development, morphogenesis/organogenesis and wound healing under physiological conditions. On the other hand, due to a broad range of substrates and the widespread distribution of these proteinases, the excessive action of MMP, ADAM and ADAMTS contributes to multiple pathological neoplastic and non-neoplastic events. The non-neoplastic conditions relate to general pathological conditions such as tissue destruction and repair, inflammation, granulation, immune reactions, infection and angiogenesis in almost all organ systems (Fig. 4).

Figure 4
Effects of matrix metalloproteinases (MMP), a disintegrin and metalloproteinases (ADAM), and a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTS) and their involvement in biological and pathological conditions. These metalloproteinases ...

One of the ultimate goals in MMP research is to demonstrate improvement of disease through the treatment of patients with MMP inhibitors. In fact, broad-spectrum and more selectively active site-directed synthetic MMP inhibitors which abrogate the proteolytic activity by binding to the zinc atom in the catalytic site, have been developed by several pharmaceutical companies and administered to patients with cancer in clinical trials. Unfortunately, however, these trials were inappropriately rushed and failed as they were carried out without information on the activity of MMP acting locally in the cancer tissue of individual patients and possible inappropriate timing and dosing regimens. Therefore, therapy was not properly targeted to the activity of a single MMP. Although the results of the trials were disappointing, it became apparent that the biological functions of MMP are complicated and that ADAM and ADAMTS have more critical biological functions within the tissue than expected. Therefore, deliberate and detailed analyses of the function of MMP, ADAM and ADAMTS and the relationship to biology and disease are needed in order for the inhibitors to be applied in future clinical trials.

ACKNOWLEDGMENTS

This work was supported by a Grant-in-Aid for Scientific Research (S) from the Ministry of Education, Science and Culture of Japan (19109004) to Y.O.

REFERENCES

1. Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2:161–174. [PubMed]
2. Mochizuki S, Okada Y. ADAM in cancer cell proliferation and progression. Cancer Sci. 2007;98:621–628. [PubMed]
3. Murphy G. The ADAM: Signalling scissors in the tumour microenvironment. Nat Rev Cancer. 2008;8:929–941. [PubMed]
4. Shiomi T, Okada Y. MT1-MMP and MMP-7 in invasion and metastasis of human cancers. Cancer Metastasis Rev. 2003;22:145–152. [PubMed]
5. Itoh Y, Seiki M. MT1-MMP: A potent modifier of pericellular microenvironment. J Cell Physiol. 2006;206:1–8. [PubMed]
6. Seiki M. The cell surface: The stage for matrix metalloproteinase regulation of migration. Curr Opin Cell Biol. 2002;14:624–632. [PubMed]
7. Ohuchi E, Imai K, Fujii Y, Sato H, Seiki M, Okada Y. Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. J Biol Chem. 1997;272:2446–2451. [PubMed]
8. Okada Y. Proteinases and matrix degradation. In: Firestein GS, Budd RC, Harris ED Jr, McInnes IB, Ruddy S, Sergent JS, editors. Kelly’s Texbook of Rheumatology. 8th edn. Philadelphia, PA: Saunders Elsevier; 2009. pp. 115–134.
9. Carmeliet P, Moons L, Lijnen R, et al. Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nat Genet. 1997;17:439–444. [PubMed]
10. Edwards DR, Handsley MM, Pennington CJ. The ADAM metalloproteinases. Mol Aspects Med. 2008;29:258–289. [PubMed]
11. Seals DF, Courtneidge SA. The ADAM family of metalloproteases: Multidomain proteins with multiple functions. Genes Dev. 2003;17:7–30. [PubMed]
12. Takeda S, Igarashi T, Mori H, Araki S. Crystal structures of VAP1 reveal ADAM’ MDC domain architecture and its unique C-shaped scaffold. EMBO J. 2006;25:2388–2396. [PMC free article] [PubMed]
13. Sahin U, Weskamp G, Kelly K, et al. Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands. J Cell Biol. 2004;164:769–779. [PMC free article] [PubMed]
14. Izumi Y, Hirata M, Hasuwa H, et al. A metalloprotease-disintegrin, MDC9/meltrin-gamma/ADAM9 and PKCdelta are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. EMBO J. 1998;17:7260–7272. [PMC free article] [PubMed]
15. Millichip MI, Dallas DJ, Wu E, Dale S, McKie N. The metallo-disintegrin ADAM10 (MADM) from bovine kidney has type IV collagenase activity in vitro . Biochem Biophys Res Commun. 1998;245:594–598. [PubMed]
16. Roy R, Wewer UM, Zurakowski D, Pories SE, Moses MA. ADAM 12 cleaves extracellular matrix proteins and correlates with cancer status and stage. J Biol Chem. 2004;279:51323–51330. [PubMed]
17. Martin J, Eynstone LV, Davies M, Williams JD, Steadman R. The role of ADAM 15 in glomerular mesangial cell migration. J Biol Chem. 2002;277:33683–33689. [PubMed]
18. Mochizuki S, Shimoda M, Shiomi T, Fujii Y, Okada Y. ADAM28 is activated by MMP-7 (matrilysin-1) and cleaves insulin-like growth factor binding protein-3. Biochem Biophys Res Commun. 2004;315:79–84. [PubMed]
19. Porter S, Clark IM, Kevorkian L, Edwards DR. The ADAMTS metalloproteinases. Biochem J. 2005;386:15–27. [PMC free article] [PubMed]
20. Novak U. ADAM proteins in the brain. J Clin Neurosci. 2004;11:227–235. [PubMed]
21. Silver DL, Hou L, Somerville R, Young ME, Apte SS, Pavan WJ. The secreted metalloprotease ADAMTS20 is required for melanoblast survival. PLoS Genet. 2008;4:e1000003. [PMC free article] [PubMed]
22. Zeng W, Corcoran C, Collins-Racie LA, Lavallie ER, Morris EA, Flannery CR. Glycosaminoglycan-binding properties and aggrecanase activities of truncated ADAMTS: Comparative analyses with ADAMTS-5, −9, −16 and −18. Biochim Biophys Acta. 2006;1760:517–524. [PubMed]
23. Tortorella MD, Burn TC, Pratta MA, et al. Purification and cloning of aggrecanase-1: A member of the ADAMTS family of proteins. Science. 1999;284:1664–1666. [PubMed]
24. Tortorella MD, Pratta M, Liu RQ, et al. Sites of aggrecan cleavage by recombinant human aggrecanase-1 (ADAMTS-4) J Biol Chem. 2000;275:18566–18573. [PubMed]
25. Nakamura H, Fujii Y, Inoki I, et al. Brevican is degraded by matrix metalloproteinases and aggrecanase-1 (ADAMTS4) at different sites. J Biol Chem. 2000;275:38885–38890. [PubMed]
26. Sandy JD, Westling J, Kenagy RD, et al. Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. J Biol Chem. 2001;276:13372–13378. [PubMed]
27. Levy GG, Nichols WC, Lian EC, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001;413:488–494. [PubMed]
28. Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMP. Cardiovasc Res. 2006;69:562–573. [PubMed]
29. Muraguchi T, Takegami Y, Ohtsuka T, et al. RECK modulates Notch signaling during cortical neurogenesis by regulating ADAM10 activity. Nat Neurosci. 2007;10:838–845. [PubMed]
30. Oh J, Takahashi R, Kondo S, et al. The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell. 2001;107:789–800. [PubMed]
31. Spinale FG. Myocardial matrix remodeling and the matrix metalloproteinases: Influence on cardiac form and function. Physiol Rev. 2007;87:1285–1342. [PubMed]
32. Kim HE, Dalal SS, Young E, Legato MJ, Weisfeldt ML, D’Armiento J. Disruption of the myocardial extracellular matrix leads to cardiac dysfunction. J Clin Invest. 2000;106:857–866. [PMC free article] [PubMed]
33. Heymans S, Luttun A, Nuyens D, et al. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nat Med. 1999;5:1135–1142. [PubMed]
34. Matsumura S, Iwanaga S, Mochizuki S, Okamoto H, Ogawa S, Okada Y. Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice. J Clin Invest. 2005;115:599–609. [PMC free article] [PubMed]
35. Ducharme A, Frantz S, Aikawa M, et al. Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J Clin Invest. 2000;106:55–62. [PMC free article] [PubMed]
36. Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868–874. [PubMed]
37. Libby P, Aikawa M, Jain MK. Vascular endothelium and atherosclerosis. Handb Exp Pharmacol. 2006:285–306. [PubMed]
38. Henney AM, Wakeley PR, Davies MJ, et al. Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. Proc Natl Acad Sci USA. 1991;88:8154–8158. [PMC free article] [PubMed]
39. Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: The good, the bad, and the ugly. Circ Res. 2002;90:251–262. [PubMed]
40. Shah PK, Falk E, Badimon JJ, et al. Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques. Potential role of matrix-degrading metalloproteinases and implications for plaque rupture. Circulation. 1995;92:1565–1569. [PubMed]
41. Galis ZS, Sukhova GK, Kranzhofer R, Clark S, Libby P. Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. Proc Natl Acad Sci USA. 1995;92:402–406. [PMC free article] [PubMed]
42. Breslow JL. Mouse models of atherosclerosis. Science. 1996;272:685–688. [PubMed]
43. Lemaitre V, O’Byrne TK, Borczuk AC, Okada Y, Tall AR, D’Armiento J. ApoE knockout mice expressing human matrix metalloproteinase-1 in macrophages have less advanced atherosclerosis. J Clin Invest. 2001;107:1227–1234. [PMC free article] [PubMed]
44. Silence J, Lupu F, Collen D, Lijnen HR. Persistence of atherosclerotic plaque but reduced aneurysm formation in mice with stromelysin-1 (MMP-3) gene inactivation. Arterioscler Thromb Vasc Biol. 2001;21:1440–1445. [PubMed]
45. Johnson J, Carson K, Williams H, et al. Plaque rupture after short periods of fat feeding in the apolipoprotein E-knockout mouse: Model characterization and effects of pravastatin treatment. Circulation. 2005;111:1422–1430. [PubMed]
46. Ye S, Eriksson P, Hamsten A, Kurkinen M, Humphries SE, Henney AM. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem. 1996;271:13055–13060. [PubMed]
47. Yamada S, Wang KY, Tanimoto A, et al. Matrix metalloproteinase 12 accelerates the initiation of atherosclerosis and stimulates the progression of fatty streaks to fibrous plaques in transgenic rabbits. Am J Pathol. 2008;172:1419–1429. [PMC free article] [PubMed]
48. Kuzuya M, Nakamura K, Sasaki T, Cheng XW, Itohara S, Iguchi A. Effect of MMP-2 deficiency on atherosclerotic lesion formation in apoE-deficient mice. Arterioscler Thromb Vasc Biol. 2006;26:1120–1225. [PubMed]
49. Laxton RC, Hu Y, Duchene J, et al. A role of matrix metalloproteinase-8 in atherosclerosis. Circ Res. 2009;105:921–929. [PMC free article] [PubMed]
50. Deguchi JO, Aikawa E, Libby P, et al. Matrix metalloproteinase-13/collagenase-3 deletion promotes collagen accumulation and organization in mouse atherosclerotic plaques. Circulation. 2005;112:2708–2715. [PubMed]
51. Schneider F, Sukhova GK, Aikawa M, et al. Matrix-metalloproteinase-14 deficiency in bone-marrow-derived cells promotes collagen accumulation in mouse atherosclerotic plaques. Circulation. 2008;117:931–939. [PubMed]
52. Zhang B, Ye S, Herrmann SM, et al. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation. 1999;99:1788–1794. [PubMed]
53. Luttun A, Lutgens E, Manderveld A, et al. Loss of matrix metalloproteinase-9 or matrix metalloproteinase-12 protects apolipoprotein E-deficient mice against atherosclerotic media destruction but differentially affects plaque growth. Circulation. 2004;109:1408–1414. [PubMed]
54. Gough PJ, Gomez IG, Wille PT, Raines EW. Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice. J Clin Invest. 2006;116:59–69. [PMC free article] [PubMed]
55. de Nooijer R, Verkleij CJ, von der Thusen JH, et al. Lesional overexpression of matrix metalloproteinase-9 promotes intraplaque hemorrhage in advanced lesions but not at earlier stages of atherogenesis. Arterioscler Thromb Vasc Biol. 2006;26:340–346. [PubMed]
56. Morishige K, Shimokawa H, Matsumoto Y, et al. Overexpression of matrix metalloproteinase-9 promotes intravascular thrombus formation in porcine coronary arteries in vivo . Cardiovasc Res. 2003;57:572–585. [PubMed]
57. Johnson JL, George SJ, Newby AC, Jackson CL. Divergent effects of matrix metalloproteinases 3, 7, 9, and 12 on atherosclerotic plaque stability in mouse brachiocephalic arteries. Proc Natl Acad Sci USA. 2005;102:15575–15580. [PMC free article] [PubMed]
58. Lemaitre V, Kim HE, Forney-Prescott M, Okada Y, D’Armiento J. Transgenic expression of matrix metalloproteinase-9 modulates collagen deposition in a mouse model of atherosclerosis. Atherosclerosis. 2009;205:107–112. [PubMed]
59. Al-Fakhri N, Wilhelm J, Hahn M, et al. Increased expression of disintegrin-metalloproteinases ADAM-15 and ADAM-9 following upregulation of integrins alpha5beta1 and alphavbeta3 in atherosclerosis. J Cell Biochem. 2003;89:808–823. [PubMed]
60. Holdt LM, Thiery J, Breslow JL, Teupser D. Increased ADAM17 mRNA expression and activity is associated with atherosclerosis resistance in LDL-receptor deficient mice. Arterioscler Thromb Vasc Biol. 2008;28:1097–1103. [PMC free article] [PubMed]
61. Jonsson-Rylander AC, Nilsson T, Fritsche-Danielson R, et al. Role of ADAMTS-1 in atherosclerosis: Remodeling of carotid artery, immunohistochemistry, and proteolysis of versican. Arterioscler Thromb Vasc Biol. 2005;25:180–185. [PubMed]
62. Wang L, Zheng J, Bai X, et al. ADAMTS-7 mediates vascular smooth muscle cell migration and neointima formation in balloon-injured rat arteries. Circ Res. 2009;104:688–698. [PubMed]
63. Thompson RW, Geraghty PJ, Lee JK. Abdominal aortic aneurysms: Basic mechanisms and clinical implications. Curr Probl Surg. 2002;39:110–230. [PubMed]
64. Choke E, Cockerill G, Wilson WR, et al. A review of biological factors implicated in abdominal aortic aneurysm rupture. Eur J Vasc Endovasc Surg. 2005;30:227–244. [PubMed]
65. Knox JB, Sukhova GK, Whittemore AD, Libby P. Evidence for altered balance between matrix metalloproteinases and their inhibitors in human aortic diseases. Circulation. 1997;95:205–212. [PubMed]
66. Freestone T, Turner RJ, Coady A, Higman DJ, Greenhalgh RM, Powell JT. Inflammation and matrix metalloproteinases in the enlarging abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol. 1995;15:1145–1151. [PubMed]
67. McMillan WD, Patterson BK, Keen RR, Pearce WH. In situ localization and quantification of seventy-two-kilodalton type IV collagenase in aneurysmal, occlusive, and normal aorta. J Vasc Surg. 1995;22:295–305. [PubMed]
68. Carrell TW, Burnand KG, Wells GM, Clements JM, Smith A. Stromelysin-1 (matrix metalloproteinase-3) and tissue inhibitor of metalloproteinase-3 are overexpressed in the wall of abdominal aortic aneurysms. Circulation. 2002;105:477–482. [PubMed]
69. Thompson RW, Holmes DR, Mertens RA, et al. Production and localization of 92-kilodalton gelatinase in abdominal aortic aneurysms. An elastolytic metalloproteinase expressed by aneurysm-infiltrating macrophages. J Clin Invest. 1995;96:318–326. [PMC free article] [PubMed]
70. McMillan WD, Patterson BK, Keen RR, Shively VP, Cipollone M, Pearce WH. In situ localization and quantification of mRNA for 92-kD type IV collagenase and its inhibitor in aneurysmal, occlusive, and normal aorta. Arterioscler Thromb Vasc Biol. 1995;15:1139–1144. [PubMed]
71. Curci JA, Liao S, Huffman MD, Shapiro SD, Thompson RW. Expression and localization of macrophage elastase (matrix metalloproteinase-12) in abdominal aortic aneurysms. J Clin Invest. 1998;102:1900–1910. [PMC free article] [PubMed]
72. Tromp G, Gatalica Z, Skunca M, et al. Elevated expression of matrix metalloproteinase-13 in abdominal aortic aneurysms. Ann Vasc Surg. 2004;18:414–420. [PubMed]
73. Annabi B, Shedid D, Ghosn P, et al. Differential regulation of matrix metalloproteinase activities in abdominal aortic aneurysms. J Vasc Surg. 2002;35:539–546. [PubMed]
74. Wilson WR, Anderton M, Schwalbe EC, et al. Matrix metalloproteinase-8 and −9 are increased at the site of abdominal aortic aneurysm rupture. Circulation. 2006;113:438–445. [PubMed]
75. Daugherty A, Cassis LA. Mouse models of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol. 2004;24:429–434. [PubMed]
76. Pyo R, Lee JK, Shipley JM, et al. Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms. J Clin Invest. 2000;105:1641–1649. [PMC free article] [PubMed]
77. Longo GM, Xiong W, Greiner TC, Zhao Y, Fiotti N, Baxter BT. Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest. 2002;110:625–632. [PMC free article] [PubMed]
78. Gong Y, Hart E, Shchurin A, Hoover-Plow J. Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice. J Clin Invest. 2008;118:3012–3024. [PMC free article] [PubMed]
79. Ikonomidis JS, Gibson WC, Butler JE, et al. Effects of deletion of the tissue inhibitor of matrix metalloproteinases-1 gene on the progression of murine thoracic aortic aneurysms. Circulation. 2004;110:II268–II273. [PubMed]
80. Xiong W, Knispel R, MacTaggart J, Baxter BT. Effects of tissue inhibitor of metalloproteinase 2 deficiency on aneurysm formation. J Vasc Surg. 2006;44:1061–1066. [PubMed]
81. Xiong W, Knispel R, MacTaggart J, Greiner TC, Weiss SJ, Baxter BT. Membrane-type 1 matrix metalloproteinase regulates macrophage-dependent elastolytic activity and aneurysm formation in vivo. J Biol Chem. 2009;284:1765–1771. [PMC free article] [PubMed]
82. Lemaitre V, Soloway PD, D’Armiento J. Increased medial degradation with pseudo-aneurysm formation in apolipoprotein E-knockout mice deficient in tissue inhibitor of metalloproteinases-1. Circulation. 2003;107:333–338. [PubMed]
83. Silence J, Collen D, Lijnen HR. Reduced atherosclerotic plaque but enhanced aneurysm formation in mice with inactivation of the tissue inhibitor of metalloproteinase-1 (TIMP-1) gene. Circ Res. 2002;90:897–903. [PubMed]
84. Lomas DA, Mahadeva R. Alpha1-antitrypsin polymerization and the serpinopathies: Pathobiology and prospects for therapy. J Clin Invest. 2002;110:1585–1590. [PMC free article] [PubMed]
85. D’Armiento J, Dalal SS, Okada Y, Berg RA, Chada K. Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema. Cell. 1992;71:955–961. [PubMed]
86. Finlay GA, O’Driscoll LR, Russell KJ, et al. Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am J Respir Crit Care Med. 1997;156:240–247. [PubMed]
87. Mercer BA, Kolesnikova N, Sonett J, D’Armiento J. Extracellular regulated kinase/mitogen activated protein kinase is upregulated in pulmonary emphysema and mediates matrix metalloproteinase-1 induction by cigarette smoke. J Biol Chem. 2004;279:17690–17696. [PubMed]
88. Imai K, Dalal SS, Chen ES, et al. Human collagenase (matrix metalloproteinase-1) expression in the lungs of patients with emphysema. Am J Respir Crit Care Med. 2001;163:786–791. [PubMed]
89. Houghton AM, Hartzell WO, Robbins CS, Gomis-Ruth FX, Shapiro SD. Macrophage elastase kills bacteria within murine macrophages. Nature. 2009;460:637–641. [PMC free article] [PubMed]
90. Segura-Valdez L, Pardo A, Gaxiola M, Uhal BD, Becerril C, Selman M. Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD. Chest. 2000;117:684–694. [PubMed]
91. Hunninghake GM, Cho MH, Tesfaigzi Y, et al. MMP12, lung function, and COPD in high-risk populations. N Engl J Med. 2009;361:2599–2608. [PMC free article] [PubMed]
92. Kawaguchi M, Kokubu F, Kuga H, et al. Modulation of bronchial epithelial cells by IL-17. J Allergy Clin Immunol. 2001;108:804–809. [PubMed]
93. Russell RE, Thorley A, Culpitt SV, et al. Alveolar macrophage-mediated elastolysis: Roles of matrix metalloproteinases, cysteine, and serine proteases. Am J Physiol Lung Cell Mol Physiol. 2002;283:L867–L873. [PubMed]
94. Foronjy R, Nkyimbeng T, Wallace A, et al. Transgenic expression of matrix metalloproteinase-9 causes adult-onset emphysema in mice associated with the loss of alveolar elastin. Am J Physiol Lung Cell Mol Physiol. 2008;294:L1149–L1157. [PubMed]
95. Atkinson JJ, Senior RM. Matrix metalloproteinase-9 in lung remodeling. Am J Respir Cell Mol Biol. 2003;28:12–24. [PubMed]
96. Sadeghnejad A, Ohar JA, Zheng SL, et al. Adam33 polymorphisms are associated with COPD and lung function in long-term tobacco smokers. Respir Res. 2009;10:21. [PMC free article] [PubMed]
97. van Diemen CC, Postma DS, Vonk JM, Bruinenberg M, Schouten JP, Boezen HM. A disintegrin and metalloprotease 33 polymorphisms and lung function decline in the general population. Am J Respir Crit Care Med. 2005;172:329–333. [PubMed]
98. Gosman MM, Boezen HM, van Diemen CC, et al. A disintegrin and metalloprotease 33 and chronic obstructive pulmonary disease pathophysiology. Thorax. 2007;62:242–247. [PMC free article] [PubMed]
99. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–1349. [PubMed]
100. Ricou B, Nicod L, Lacraz S, Welgus HG, Suter PM, Dayer JM. Matrix metalloproteinases and TIMP in acute respiratory distress syndrome. Am J Respir Crit Care Med. 1996;154:346–352. [PubMed]
101. Torii K, Iida K, Miyazaki Y, et al. Higher concentrations of matrix metalloproteinases in bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome. Am J Respir Crit Care Med. 1997;155:43–46. [PubMed]
102. Pardo A, Selman M, Ridge K, Barrios R, Sznajder JI. Increased expression of gelatinases and collagenase in rat lungs exposed to 100% oxygen. Am J Respir Crit Care Med. 1996;154:1067–1075. [PubMed]
103. Armstrong L, Thickett DR, Mansell JP, et al. Changes in collagen turnover in early acute respiratory distress syndrome. Am J Respir Crit Care Med. 1999;160:1910–1915. [PubMed]
104. Pugin J, Verghese G, Widmer MC, Matthay MA. The alveolar space is the site of intense inflammatory and profibrotic reactions in the early phase of acute respiratory distress syndrome. Crit Care Med. 1999;27:304–312. [PubMed]
105. Warner RL, Beltran L, Younkin EM, et al. Role of stromelysin 1 and gelatinase B in experimental acute lung injury. Am J Respir Cell Mol Biol. 2001;24:537–544. [PubMed]
106. Warner RL, Lewis CS, Beltran L, Younkin EM, Varani J, Johnson KJ. The role of metalloelastase in immune complex-induced acute lung injury. Am J Pathol. 2001;158:2139–2144. [PMC free article] [PubMed]
107. Gipson TS, Bless NM, Shanley TP, et al. Regulatory effects of endogenous protease inhibitors in acute lung inflammatory injury. J Immunol. 1999;162:3653–3662. [PubMed]
108. Martin EL, Moyer BZ, Pape MC, Starcher B, Leco KJ, Veldhuizen RA. Negative impact of tissue inhibitor of metalloproteinase-3 null mutation on lung structure and function in response to sepsis. Am J Physiol Lung Cell Mol Physiol. 2003;285:L1222–L1232. [PubMed]
109. Carney DE, Lutz CJ, Picone AL, et al. Matrix metalloproteinase inhibitor prevents acute lung injury after cardiopulmonary bypass. Circulation. 1999;100:400–406. [PubMed]
110. Carney DE, McCann UG, Schiller HJ, et al. Metalloproteinase inhibition prevents acute respiratory distress syndrome. J Surg Res. 2001;99:245–252. [PubMed]
111. Steinberg J, Halter J, Schiller HJ, et al. Metalloproteinase inhibition reduces lung injury and improves survival after cecal ligation and puncture in rats. J Surg Res. 2003;111:185–195. [PubMed]
112. Zuo F, Kaminski N, Eugui E, et al. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc Natl Acad Sci USA. 2002;99:6292–6297. [PMC free article] [PubMed]
113. Fujishima S, Shiomi T, Yamashita S, et al. Production and activation of matrix metalloproteinase 7 (Matrilysin 1) in the lungs of patients with idiopathic pulmonary fibrosis. Arch Pathol Lab Med. 2010 (in press). [PubMed]
114. Keating DT, Sadlier DM, Patricelli A, et al. Microarray identifies ADAM family members as key responders to TGF-beta1 in alveolar epithelial cells. Respir Res. 2006;7:114. [PMC free article] [PubMed]
115. Mautino G, Oliver N, Chanez P, Bousquet J, Capony F. Increased release of matrix metalloproteinase-9 in bronchoalveolar lavage fluid and by alveolar macrophages of asthmatics. Am J Respir Cell Mol Biol. 1997;17:583–591. [PubMed]
116. Rajah R, Nachajon RV, Collins MH, Hakonarson H, Grunstein MM, Cohen P. Elevated levels of the IGF-binding protein protease MMP-1 in asthmatic airway smooth muscle. Am J Respir Cell Mol Biol. 1999;20:199–208. [PubMed]
117. Zhang D, Bar-Eli M, Meloche S, Brodt P. Dual regulation of MMP-2 expression by the type 1 insulin-like growth factor receptor: The phosphatidylinositol 3-kinase/Akt and Raf/ERK pathways transmit opposing signals. J Biol Chem. 2004;279:19683–19690. [PubMed]
118. Gueders MM, Foidart JM, Noel A, Cataldo DD. Matrix metalloproteinases (MMP) and tissue inhibitors of MMP in the respiratory tract: Potential implications in asthma and other lung diseases. Eur J Pharmacol. 2006;533:133–144. [PubMed]
119. Van Eerdewegh P, Little RD, Dupuis J, et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature. 2002;418:426–430. [PubMed]
120. Chang JC, Wysocki A, Tchou-Wong KM, Moskowitz N, Zhang Y, Rom WN. Effect of Mycobacterium tuberculosis and its components on macrophages and the release of matrix metalloproteinases. Thorax. 1996;51:306–311. [PMC free article] [PubMed]
121. Hrabec E, Strek M, Zieba M, Kwiatkowska S, Hrabec Z. Circulation level of matrix metalloproteinase-9 is correlated with disease severity in tuberculosis patients. Int J Tuberc Lung Dis. 2002;6:713–719. [PubMed]
122. Elkington PT, Nuttall RK, Boyle JJ, et al. Mycobacterium tuberculosis, but not vaccine BCG, specifically upregulates matrix metalloproteinase-1. Am J Respir Crit Care Med. 2005;172:1596–1604. [PubMed]
123. Agrawal SM, Lau L, Yong VW. MMP in the central nervous system: Where the good guys go bad. Semin Cell Dev Biol. 2008;19:42–51. [PubMed]
124. Albright AV, Shieh JT, Itoh T, et al. Microglia express CCR5, CXCR4, and CCR3, but of these, CCR5 is the principal coreceptor for human immunodeficiency virus type 1 dementia isolates. J Virol. 1999;73:205–213. [PMC free article] [PubMed]
125. Gray F, Chretien F, Vallat-Decouvelaere AV, Scaravilli F. The changing pattern of HIV neuropathology in the HAART era. J Neuropathol Exp Neurol. 2003;62:429–440. [PubMed]
126. Eugenin EA, Osiecki K, Lopez L, Goldstein H, Calderon TM, Berman JW. CCL2/monocyte chemoattractant protein-1 mediates enhanced transmigration of human immunodeficiency virus (HIV)-infected leukocytes across the blood-brain barrier: A potential mechanism of HIV-CNS invasion and NeuroAIDS. J Neurosci. 2006;26:1098–1106. [PubMed]
127. Chong YH, Seoh JY, Park HK. Increased activity of matrix metalloproteinase-2 in human glial and neuronal cell lines treated with HIV-1 gp41 peptides. J Mol Neurosci. 1998;10:129–141. [PubMed]
128. Noble LJ, Donovan F, Igarashi T, Goussev S, Werb Z. Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events. J Neurosci. 2002;22:7526–7535. [PMC free article] [PubMed]
129. Wells JE, Rice TK, Nuttall RK, et al. An adverse role for matrix metalloproteinase 12 after spinal cord injury in mice. J Neurosci. 2003;23:10107–10115. [PubMed]
130. Rosenberg GA. Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol. 2009;8:205–216. [PubMed]
131. Adair JC, Charlie J, Dencoff JE, et al. Measurement of gelatinase B (MMP-9) in the cerebrospinal fluid of patients with vascular dementia and Alzheimer disease. Stroke. 2004;35:e159–e162. [PubMed]
132. Buxbaum JD, Liu KN, Luo Y, et al. Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem. 1998;273:27765–27767. [PubMed]
133. Lorenzl S, Albers DS, Relkin N, et al. Increased plasma levels of matrix metalloproteinase-9 in patients with Alzheimer’s disease. Neurochem Int. 2003;43:191–196. [PubMed]
134. Bernstein HG, Bukowska A, Krell D, Bogerts B, Ansorge S, Lendeckel U. Comparative localization of ADAM 10 and 15 in human cerebral cortex normal aging, Alzheimer disease and Down syndrome. J Neurocytol. 2003;32:153–160. [PubMed]
135. Kim YS, Kim SS, Cho JJ, et al. Matrix metalloproteinase-3: A novel signaling proteinase from apoptotic neuronal cells that activates microglia. J Neurosci. 2005;25:3701–3711. [PubMed]
136. Choi DH, Kim EM, Son HJ, et al. A novel intracellular role of matrix metalloproteinase-3 during apoptosis of dopaminergic cells. J Neurochem. 2008;106:405–415. [PubMed]
137. Arthur MJ, Fibrogenesis II. Metalloproteinases and their inhibitors in liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 2000;279:G245–G249. [PubMed]
138. Uchinami H, Seki E, Brenner DA, D’Armiento J. Loss of MMP 13 attenuates murine hepatic injury and fibrosis during cholestasis. Hepatology. 2006;44:420–429. [PubMed]
139. Schwettmann L, Wehmeier M, Jokovic D, et al. Hepatic expression of A disintegrin and metalloproteinase (ADAM) and ADAM with thrombospondin motives (ADAM-TS) enzymes in patients with chronic liver diseases. J Hepatol. 2008;49:243–250. [PubMed]
140. Viappiani S, Sariahmetoglu M, Schulz R. The role of matrix metalloproteinase inhibitors in ischemia-reperfusion injury in the liver. Curr Pharm Des. 2006;12:2923–2934. [PubMed]
141. Keck T, Jargon D, Klunsch A, et al. MMP-9 in serum correlates with the development of pulmonary complications in experimental acute pancreatitis. Pancreatology. 2006;6:316–322. [PubMed]
142. Catania JM, Chen G, Parrish AR. Role of matrix metalloproteinases in renal pathophysiologies. Am J Physiol Renal Physiol. 2007;292:F905–F911. [PubMed]
143. Caron A, Desrosiers RR, Beliveau R. Ischemia injury alters endothelial cell properties of kidney cortex: Stimulation of MMP-9. Exp Cell Res. 2005;310:105–116. [PubMed]
144. Carome MA, Striker LJ, Peten EP, et al. Human glomeruli express TIMP-1 mRNA and TIMP-2 protein and mRNA. Am J Physiol. 1993;264:F923–F929. [PubMed]
145. Chang HR, Yang SF, Li ML, Lin CC, Hsieh YS, Lian JD. Relationships between circulating matrix metalloproteinase-2 and −9 and renal function in patients with chronic kidney disease. Clin Chim Acta. 2006;366:243–248. [PubMed]
146. Inada A, Nagai K, Arai H, et al. Establishment of a diabetic mouse model with progressive diabetic nephropathy. Am J Pathol. 2005;167:327–336. [PMC free article] [PubMed]
147. McLennan SV, Kelly DJ, Cox AJ, et al. Decreased matrix degradation in diabetic nephropathy: Effects of ACE inhibition on the expression and activities of matrix metalloproteinases. Diabetologia. 2002;45:268–275. [PubMed]
148. Del Prete D, Anglani F, Forino M, et al. Downregulation of glomerular matrix metalloproteinase-2 gene in human NIDDM. Diabetologia. 1997;40:1449–1454. [PubMed]
149. Han SY, Jee YH, Han KH, et al. An imbalance between matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase-2 contributes to the development of early diabetic nephropathy. Nephrol Dial Transplant. 2006;21:2406–2416. [PubMed]
150. Kanauchi M, Nishioka H, Nakashima Y, Hashimoto T, Dohi K. Role of tissue inhibitors of metalloproteinase in diabetic nephropathy. Nippon Jinzo Gakkai Shi. 1996;38:124–128. [PubMed]
151. Ebihara I, Nakamura T, Shimada N, Koide H. Increased plasma metalloproteinase-9 concentrations precede development of microalbuminuria in non-insulin-dependent diabetes mellitus. Am J Kidney Dis. 1998;32:544–550. [PubMed]
152. Tashiro K, Koyanagi I, Ohara I, et al. Levels of urinary matrix metalloproteinase-9 (MMP-9) and renal injuries in patients with type 2 diabetic nephropathy. J Clin Lab Anal. 2004;18:206–210. [PubMed]
153. Romanic AM, Burns-Kurtis CL, Ao Z, Arleth AJ, Ohlstein EH. Upregulated expression of human membrane type-5 matrix metalloproteinase in kidneys from diabetic patients. Am J Physiol Renal Physiol. 2001;281:F309–F317. [PubMed]
154. Ewens KG, George RA, Sharma K, Ziyadeh FN, Spielman RS. Assessment of 115 candidate genes for diabetic nephropathy by transmission/disequilibrium test. Diabetes. 2005;54:3305–3318. [PubMed]
155. Gill SE, Parks WC. Metalloproteinases and their inhibitors: Regulators of wound healing. Int J Biochem Cell Biol. 2008;40:1334–1347. [PMC free article] [PubMed]
156. Dumin JA, Dickeson SK, Stricker TP, et al. Pro-collagenase-1 (matrix metalloproteinase-1) binds the alpha(2)beta(1) integrin upon release from keratinocytes migrating on type I collagen. J Biol Chem. 2001;276:29368–29374. [PubMed]
157. Hattori N, Mochizuki S, Kishi K, et al. MMP-13 plays a role in keratinocyte migration, angiogenesis, and contraction in mouse skin wound healing. Am J Pathol. 2009;175:533–546. [PMC free article] [PubMed]
158. Li CK, Pender SL, Pickard KM, et al. Impaired immunity to intestinal bacterial infection in stromelysin-1 (matrix metalloproteinase-3)-deficient mice. J Immunol. 2004;173:5171–5179. [PubMed]
159. Krueger S, Hundertmark T, Kalinski T, et al. Helicobacter pylori encoding the pathogenicity island activates matrix metalloproteinase 1 in gastric epithelial cells via JNK and ERK. J Biol Chem. 2006;281:2868–2875. [PubMed]
160. Fujita Y, Shiomi T, Yanagimoto S, Matsumoto H, Toyama Y, Okada Y. Tetraspanin CD151 is expressed in osteoarthritic cartilage and is involved in pericellular activation of pro-matrix metalloproteinase 7 in osteoarthritic chondrocytes. Arthritis Rheum. 2006;54:3233–3243. [PubMed]
161. Neuhold LA, Killar L, Zhao W, et al. Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J Clin Invest. 2001;107:35–44. [PMC free article] [PubMed]
162. Clements KM, Price JS, Chambers MG, Visco DM, Poole AR, Mason RM. Gene deletion of either interleukin-1beta, interleukin-1beta-converting enzyme, inducible nitric oxide synthase, or stromelysin 1 accelerates the development of knee osteoarthritis in mice after surgical transection of the medial collateral ligament and partial medial meniscectomy. Arthritis Rheum. 2003;48:3452–3463. [PubMed]
163. Little CB, Meeker CT, Hembry RM, et al. Matrix metalloproteinases are not essential for aggrecan turnover during normal skeletal growth and development. Mol Cell Biol. 2005;25:3388–3399. [PMC free article] [PubMed]
164. Glasson SS, Askew R, Sheppard B, et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature. 2005;434:644–648. [PubMed]
165. Stanton H, Rogerson FM, East CJ, et al. ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature. 2005;434:648–652. [PubMed]
166. Naito S, Shiomi T, Okada A, et al. Expression of ADAMTS4 (aggrecanase-1) in human osteoarthritic cartilage. Pathol Int. 2007;57:703–711. [PubMed]
167. Yatabe T, Mochizuki S, Takizawa M, et al. Hyaluronan inhibits expression of ADAMTS4 (aggrecanase-1) in human osteoarthritic chondrocytes. Ann Rheum Dis. 2009;68:1051–1058. [PMC free article] [PubMed]
168. Bohm BB, Aigner T, Roy B, Brodie TA, Blobel CP, Burkhardt H. Homeostatic effects of the metalloproteinase disintegrin ADAM15 in degenerative cartilage remodeling. Arthritis Rheum. 2005;52:1100–1109. [PubMed]
169. Okada A, Mochizuki S, Yatabe T, et al. ADAM-12 (meltrin alpha) is involved in chondrocyte proliferation via cleavage of insulin-like growth factor binding protein 5 in osteoarthritic cartilage. Arthritis Rheum. 2008;58:778–789. [PubMed]
170. Yoshihara Y, Nakamura H, Obata K, et al. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids from patients with rheumatoid arthritis or osteoarthritis. Ann Rheum Dis. 2000;59:455–461. [PMC free article] [PubMed]
171. Yamanaka H, Makino K, Takizawa M, et al. Expression and tissue localization of membrane-types 1, 2, and 3 matrix metalloproteinases in rheumatoid synovium. Lab Invest. 2000;80:677–687. [PubMed]
172. Liu CJ, Kong W, Ilalov K, et al. ADAMTS-7: A metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein. FASEB J. 2006;20:988–990. [PMC free article] [PubMed]
173. Liu CJ, Kong W, Xu K, et al. ADAMTS-12 associates with and degrades cartilage oligomeric matrix protein. J Biol Chem. 2006;281:15800–15808. [PMC free article] [PubMed]
174. Komiya K, Enomoto H, Inoki I, et al. Expression of ADAM15 in rheumatoid synovium: Upregulation by vascular endothelial growth factor and possible implications for angiogenesis. Arthritis Res Ther. 2005;7:R1158–R1173. [PMC free article] [PubMed]
175. Dehmel T, Janke A, Hartung HP, Goebel HH, Wiendl H, Kieseier BC. The cell-specific expression of metalloproteinase-disintegrins (ADAM) in inflammatory myopathies. Neurobiol Dis. 2007;25:665–674. [PubMed]
176. Li H, Mittal A, Makonchuk DY, Bhatnagar S, Kumar A. Matrix metalloproteinase-9 inhibition ameliorates pathogenesis and improves skeletal muscle regeneration in muscular dystrophy. Hum Mol Genet. 2009;18:2584–2598. [PMC free article] [PubMed]
177. Jorgensen LH, Jensen CH, Wewer UM, Schroder HD. Transgenic overexpression of ADAM12 suppresses muscle regeneration and aggravates dystrophy in aged mdx mice. Am J Pathol. 2007;171:1599–1607. [PMC free article] [PubMed]
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...