InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Biochemistry, Genetics and Molecular Biology » "The Role of Matrix Metalloproteinase in Human Body Pathologies", book edited by Francesco Travascio, ISBN 978-953-51-3718-4, Print ISBN 978-953-51-3717-7, Published: December 20, 2017 under CC BY 3.0 license. © The Author(s).

Chapter 1

Overview of MMP Biology and Gene Associations in Human Diseases

By Tamara Djuric and Maja Zivkovic
DOI: 10.5772/intechopen.70265

Article top

Overview of MMP Biology and Gene Associations in Human Diseases

Tamara Djuric and Maja Zivkovic
Show details


Interactions of cell with the extracellular matrix (ECM) are crucial for normal development and functioning of the human organism. By regulating ECM integrity and composition matrix metalloproteinases (MMPs) play the main role in ECM molecules signaling and influence processes such as proliferation, migration, differentiation and apoptosis. ECM remodeling is a highly regulated process. When imbalanced it could contribute to pathophysiology of many diseases. The MMPs actions and activity are regulated through different mechanisms such as regulation of transcription, activation of latent MMPs, inhibition of MMP function by tissue inhibitors of metalloproteinases. MMPs are a family of calcium- and zinc-dependent endoproteinase, which share similar structural domains, but differs in substrate specificity, cell localizations and inducibility. Genetic variations in MMPs have been associated with a number of diseases, still not all findings are reproducible. Nine of 23 human genes encoding MMPs are located in a cluster on chromosome 11, which implicate their haplotype-driven effects. They could be important mediators of disease severity and could trigger acute events. In this chapter, we will review the basics of MMP biology and the most significant associations of MMPs variations with cardiovascular and neurological diseases in humans and MMPs therapeutic potential through synthetic inhibitors.

Keywords: MMP structure, MMP activation, MMP regulation, microRNA, MMP inhibitors, genetic variations, MMP haplotype

1. Introduction

Matrix metalloproteinases (MMPs) are a family of calcium (Ca2+)- and zinc (Zn2+)-dependent proteolytic enzymes involved in physiological as well as in pathological processes in the human organism. Initially they were thought to degrade only the extracellular matrix (ECM) components, but nowadays it is well known that they have wider substrate specificity that includes non-matrix proteins of which the vast majority are bioactive molecules. Cell-cell and cell-ECM interactions are inevitable for normal development and functioning of the organism. Various proteinases are implicated in ECM remodeling, but MMPs are playing the key role. Remodeling of the tissue is crucial for physiological processes such as development, tissue homeostasis, morphogenesis and tissue repair. It could be a part of many pathological states such as arthritis, cardiovascular diseases, neurodegenerative diseases or part of the impaired development in congenital anomalies [14]. By regulating ECM structure and composition, MMPs are involved in growth factor availability and are playing the main role in the function of cell surface signaling systems and in that way influence proliferation, migration, differentiation and apoptosis [5]. The importance of their role in the physiological functioning of the human organism entails strict regulation of the expression and the activity of MMPs. They are regulated through different mechanisms such as regulation of transcription, activation of latent MMPs, inhibition of MMP function by tissue inhibitors of metalloproteinases (TIMPS) and so on. There is growing evidence that genetic variations in MMPs can influence gene expression or protein activity. Nine of 23 human genes encoding MMPs are located in a cluster on chromosome 11 (11q22.2–11q22.3) [6], which implicate their haplotype-driven effects. It has been shown that MMPs are important mediators of disease severity or could trigger acute events. Since they are involved in a wide spectrum of physiological and pathological processes, there is a need for determination of their precise role in different tissue and cell-specific context as well as in different stages of disease development or progression. Only then the therapeutic potential through the development of the specific inhibitors could be accurately implemented. In this chapter, we will discuss the main structural, substrate and functional properties of MMPs and give a brief review of the genetic associations with cardiovascular, neurodegenerative diseases and congenital anomalies in humans.

2. Matrix metalloproteinases

MMPs or matrixins belongs to the large family of proteinases called metzincin superfamily. Regarding its structural characteristics metzincins are subdivided into five subgroups. Other members of this superfamily are adamalysins, including a disintegrin and metalloproteinase (ADAMs) and ADAM with thrombospondin-like motif (ADAMTS), astacins, serralysins and pappalysins [7]. MMPs are expressed as zinc-dependent endopeptidases and have a wide spectrum of biological substrates that are overlapping. There are 24 genes encoding MMPs in humans, including duplicated MMP-23 gene. So, there are 23 different MMPs in humans [8]. They were named as MMP by the International Union of Biochemistry and Molecular Biology and each member of the enzyme family was assigned by a number (MMP-1, -2, -3 etc.) [9]. All MMPs contains the Zn2+ binding motif, HEXXHXXGXXH, in their catalytic domain and a conserved methionine forming a ‘Met-turn’; are secreted in pro-pre enzyme form; need Ca2+ for its stability; function at neutral pH; are inhibited by TIMPs. The MMPs can be and are classified in different ways. The most common classification is based on their substrate specificity and basic domain structure. According to these criteria MMPs are subdivided into collagenases, gelatinases, stromelysins, matrilysins and membrane type-MMPs (MT-MMPs). However, there are MMPs that do not belong to any of this group specifically so they are grouped as “others” ( Figure 1 ).


Figure 1.

The domain composition and structural features of the MMPs subgroups.

2.1. Structure of MMPs

MMPs domain composition and arrangements are presented in Figure 1 . MMPs protein contains at least three homologous domains: signal peptide responsible for protein secretion, pro-peptide domain containing a consensus cysteine-switch sequence and is needed for activation of the enzyme, catalytic domain which contains a zinc-binding consensus sequence and is responsible for the proteolytic activity.

Amino-terminal signal peptide is composed of 17–29 amino acids and is responsible for targeting the enzyme to the endoplasmic reticulum and Golgi complex and for the later excretion out of the cell. The most of the MMPs are extracellular proteins except MT-MMPs that are bound to the cell surface by a transmembrane domain or glycosylphosphatidylinositol anchor.

The next, pro-peptide domain consists of 77–87 amino acids and have conserved ‘cysteine switch’ motif. All MMPs except MMP-23 have this motif. The thiol group from the unpaired cysteine molecule could bind to the Zn2+ in the catalytic domain, making the pro-MMPs inactive [10]. After the proteolytic cleavage of the bite region of the protein (serine protease, MMPs and furin) the pro-peptide domain become destabilized and the interaction between Zn2+ and cysteine disrupts which turns zymogens into the active MMP form. The modification of the cysteine thiol group with physiological (oxidation) or non-physiological agents (heavy metal ions) could lead to irreversible activation of the MMP by autolysis [11].

Catalytic domain contains approximately 170 amino acids and has the highest sequence homology between the metalloproteinases. It comprises Zn2+ binding motif HEXXHXXGXXH and a conserved methionine, forming a ‘Met-turn’. This domain contains additional Zn2+ and Ca2+ ions that maintain the three-dimensional MMP structure needed for MMPs stability and enzymatic activity [12]. MMP-2 and -9 also contains three tandem fibronectin II type repeats that are responsible for elastin and gelatin binding. Typically in MMPs, carboxy-terminal end is linked to hemopexin domain with linker peptide called ‘hinge region’. Hemopexin domain consists of about 200 amino acids and modulates substrate recognition. The MMP-7, -26 and -23 do not posses hinge region and hemopexin domain. MMP-23 has a unique carboxy terminal domain rich in cysteine and an immunoglobulin-like domain after the C terminus of the catalytic domain.

2.1.1. Collagenases

There are three collagenases: interstitial collagenase (MMP-1), neutrophil collagenase (MMP-8) and collagenase 3 (MMP-13). Their main characteristic is to cleave fibrillar collagens type-I, -II and -III at the specific site of the triple helices, specifically three-fourths from the N-terminus. In that way they are making characteristic ¼ and ¾ fragments. Beyond the fibrillar collagens they also degrade a number of ECM and non-ECM substrates ( Table 1 ).

MMPCollagenous substratesNoncollagenous ECM substratesNon-ECM substrates
MMP-1Collagen types I, II, III, VII, VIII, X and gelatinAggrecan, casein, serpins, versican, perlecan, proteoglycan link protein and tenascin-Cα1-antitrypsin/α1-antichymotrypsin, IL-1β, latent TNF-α, MCP-1,-2,-3,-4, IGFBP-2, −3, SDF-1, VEGF
MMP-2Collagen types I, IV, V, VII, X, XI, XIV and gelatinAggrecan, elastin, fibronectin, laminin, perlecan, proteoglycan link protein and versicanIL-1β, Pro-IL-1β, SDF-1, MCP-3, IGFBP-3, latent TGF-β, latent TNF-α, FGFR1, pleiotrophin, CTGF
MMP-3Collagen types II, IV, IX, X and gelatinAggrecan, casein, decorin, elastin, fibronectin, laminin, perlecan, proteoglycan, proteoglycan link protein and versicanα1-antitrypsin/α1-antichymotrypsin, IL-1β, Pro-IL-1β, MCP-1,-2,-3,-4, SDF-1, IGFBP-1, −3, latent TGF-β, latent TNF-α, Pro-HB-EGF, osteopontin, VEGF
MMP-7Collagen types I, II, III, V, VI and XAggrecan, casein, elastin, entactin, laminin and proteoglycan link proteinα1-antitrypsin, Pro-HB-EGF, Latent TNF-α, syndecan-1, osteopontin, cellular membrane bound FasL, VEGF
MMP-8Collagen types I, II, III, V, VII, VIII, X and gelatinAggrecan and lamininα1-antitrypsin, CXCL5, IL-8
MMP-9Collagen types V, VI, VII, X and XIVFibronectin, laminin, proteoglycan link protein and versicanα1-antitrypsin, IL-1β, Pro-IL-1β, CXCL5, IL-8, SDF-1, latent TGF-β, latent TNF-α, IL-2Rα, IGFBP-1, VEGF
MMP-10Collagen types II, IV, V and gelatinFibronectin and laminin
MMP-11None knownLamininα1-antitrypsin, IGFBP-1
MMP-12None knownElastinLatent TNF-α
MMP-13Collagen types I, II, III, IV, V, IX, X, XI and gelatinAggrecan, fibronectin, laminin, perlecan and tenascinα1-antichymotrypsin, latent TGF-β, latent TNF-α, MCP-3, SDF-1
MMP-14Collagen types I, II, III and gelatinAggrecan, dermatan sulfate proteoglycan, fibrin, fibronectin, laminin, perlecan, tenascin and vitronectinMCP-3, SDF-1
MMP-15Collagen types I, II, III and gelatinAggrecan, fibronectin, laminin, perlecan, tenascin and vitronectin
MMP-16Collagen types I, III and gelatinAggrecan, casein, fibronectin, laminin, perlecan and vitronectinVEGF
MMP-17GelatinFibrin and fibronectinTNF-α
MMP-19Collagen types I, IV and gelatinAggrecan, casein, fibronectin, laminin and tenascinVEGF
MMP-20Aggrecan, amelogenin and cartilage oligomeric protein
MMP-23GelatinChondroitin sulfate, dermatan sulfate and fibronectin
MMP-24GelatinFibrin and fibronectin
MMP-25Collagen type IV and gelatinCasein, fibrinogen and fibronectin
MMP-26Collagen type IV and gelatinCaseinα1-antitrypsin

Table 1.

MMP substrates.

MMP, matrix metalloproteinase; ECM, extracellular matrix; IL-1 interleukin 1; TNF, tumor necrosis factor; MCP, monocyte chemoattractant protein; IGFBP, Insulin-like growth factor-binding protein; SDF, stromal cell-derived factor; VEGF, vascular endothelial growth factor; TGF, tumor growth factor; FGFR, fibroblast growth factor receptor; CTGF, connective tissue growth factor; EGF, epidermal growth factor; CXCL5, C-X-C motif chemokine ligand 5; IL-8, interleukin 8; IL-2R, interleukin 2 receptor.

2.1.2. Gelatinases

So-called gelatinase A (MMP-2) and gelatinase B (MMP-9) belongs to this group. Both of them have three repeats of a fibronectin type-II motif in the catalytic domain. They degrade denaturated collagens as well as native collagens type-IV, -V and -XI. They also denaturate gelatins, laminin and aggrecan and number of other ECM molecules. MMP-2, but not MMP-9 could cleave collagens type-I, -II and -III [13, 14]. Nevertheless, its collagenolytic activity is weaker than that of collagenases. Still, because of ability of pro-MMP-2 to recruit to the cell surface and to be activated by the MT1-MMP, it can accumulate extracellularly and have higher collagenolytic potential locally.

2.1.3. Stromelysins

Stromelysin 1 (MMP-3), stromelysin 2 (MMP-10) and stromelysin 3 (MMP-11) belongs to this group. Their name reflects the capability of degrading the wide spectrum of ECM proteins. MMP-3 and -10 degrade proteoglycans, laminin, fibronectin, vitronectin and some types of collagens but not interstitial collagens, whereas MMP-11 has a very weak affinity for ECM molecules ( Table 1 ). It is located on chromosome 22, while MMP-3 and -10 are in the cluster with seven more genes on the chromosome 11 [6]. MMP-3 has the highest proteolytic efficiency in the group and is capable of activating many other pro-MMPs. It plays the main role in full activation of pro-MMP-1 [15].

2.1.4. Matrylisins

The main characteristic of matrylisins is that they lack hemopexin domain. MMP-7 and -26 belongs to this group. Both of them degrade ECM components, while MMP-7 degrade some of the cell surface molecules such as E cadherin, pro-tumor necrosis factor alpha, Fas ligand, syndecan 1 and pro-alpha defensin.

2.1.5. Membrane-type MMPs

There are six MT-MMPs that are divided into two groups: MMP-14, -15, -16 and -24 belongs to the type-I transmembrane proteins, while MMP-17 and MMP-25 are glycosylphosphatidylinositol-anchored proteins. All of them have a furin-like proprotein convertase recognition sequence and are activated intracellularly. All, but MT4-MMP, can activate pro-MMP2 [16]. They degrade ECM molecules, whereas MT1-MMP14 can cleave collagen type-I, -II and -III [17] and can activate proMMP-13 on the cell surface [18].

2.1.6. Other MMPs

Seven MMPs belong to this group. Three of them (MMP-12, -20 and -27) have a similar domain arrangement and are part of the cluster of nine genes on the chromosome 11 [6]. MMP-12 is called metalloelastase. It is mainly produced in macrophages [19] but has been found in hypertrophic chondrocytes [20] and osteoclasts [21], as well. Besides elastin it degrades other ECM proteins and is essential for macrophage migration [22]. MMP-19 is expressed in human tissues [23] and degrades basement membrane as well as other ECM molecules [24]. It is involved in tissue remodeling and migration of epithelial cells by degrading laminin 5 gamma 2 chain [25]. MMP-20, enamelysin is expressed in newly formed tooth and degrades amelogenin [26]. A mutation in this gene causes genetic disorder called amelogenin imperfecta [27]. MMP-21 is expressed in human tissues. It was found in basal and squamous cell carcinomas [28]. Annotation of its action toward ECM molecules is still not known. MMP-23 is different from other MMPs because it lacks the cysteine switch motif in the prodomain and the hemopexin domain. It posses a cysteine-rich domain which is followed by an immunoglobulin-like domain. It is mainly expressed in reproductive tissues [29]. MMP-27 is expressed in B lymphocytes [30], but the function of this enzyme in mammals is not known, yet. MMP-28, or epilysin, is expressed in many human tissues [31]. It is involved in wound repair [32] and its expression was elevated in patients with osteoarthritis [33] and rheumatoid arthritis [34]. MMP-28 overexpression up-regulated MT-MMP1 and MMP-9 in A549 lung adenocarcinoma cells [35].

2.2. Regulation of MMPs

Since they have the potential to degrade ECM and wide spectrum of non-ECM substrates and to activate other MMPs or release growth factors, matrix metalloproteinases have been stringently regulated at different levels. They are regulated at a transcriptional and translational level, by activation of the zymogen forms, by the extracellular or endogenous inhibitors, by subcellular or extracellular localization and internalization by endocytosis.

Cellular expression of MMPs is based on successive activation of multiple signaling pathways leading to synergistic effects of more transcriptional factors on the MMP promoter. Some of the most important are NF-κB, activating protein (AP)-1 and Sp-1. Recent studies have shown that endogenous miRNAs are able to recognize complementary genomic sites within human gene promoters, and in that way regulate gene transcription [36, 37]. There are multiple factors that can trigger different signaling pathways modulating MMP gene expression. They could be cytokines, chemokines or growth factors such as Interleukin-1 (IL-1), Interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). The expression could also be modulated by reactive oxygen species,mechanical injury, shear or tensile stress, contact with cell bound ligands, etc. The expression of MMPs could be down-regulated by the anti inflammatory molecules such as nitric oxide (NO), transforming growth factor beta (TGF-β), Interleukin-4 (IL-4), Interleukin-10 (IL-10), interferon-γ and peroxisome proliferator-activated receptor (PPAR) (reviewed in Ref. [38]). The cell-cell and cell-matrix interactions established through adhesion molecules or integrins also have an impact on the MMPs expression [39]. Transcription could be also modified by genetic variation within the MMPs gene promoters. In the past two decades, the SNPs identified in the promoter of the MMP-1, -2, -3, -7, -9, -12, and -13 genes has been denoted as functional and associated with cardiovascular disease phenotypes (reviewed in Ref. [40]).

2.2.1. Activation of MMPs

Almost all MMPs are secreted as an inactive form. One of the mechanism of activation is, earlier mentioned, a ‘cysteine switch’ mechanism where the thiol group of the unpaired cysteine is replaced by the water. This mechanism is the first step of the stepwise activation process. It enables further pro-peptide hydroxylation of partially activated MMP or other proteases until the final step of its removal and activation [41]. Most of the MMPs are activated after the secretion, extracellularly. But the MT-MMPs and MMP-11, -23 and -28 are activated intracellularly. They have a furin recognition sequence that allows them to be activated in the Golgi apparatus by pro-protein convertase within the secretory pathway [4245]. One of the most significant activator of MMPs in vivo is considered to be a serine protease plasmin [46]. It is shown that it activates MMP-1, -3, -7, -8, -9, -10 and -13 [46]. Other serine proteases such as mast cell proteases, chymases and tryptases also have the potential to activate pro-MMPs. Human tryptase could activate pro-MMP-3 and pro-MMP-1 but the activation of the latter is dependent on the activation of the former [47, 48].

Moreover, once activated MMPs are able to activate other pro-MMPs. For example, MMP-3 could activate pro-MMP-1, -7, -8, -9 and -13. Then, activated MMP-7 could activate zymogens pro-MMP-1, -9 and -13. Pro-MMP-2 and -3 could be activated by MMP-12 as well, while MMP-2 can activate pro-MMP-9. So, a very complex network of positive feedback loops exist and it could trigger proteolytic cleavage of the complete ECM ( Figure 2 ). That is why the strict and multilevel regulation of MMPs must exist for the physiological functioning of the human organism. Inactive form of MMP-2 has somewhat specific activating mechanism which involves MT1-MMP and TIMP-2 [49]. Long story short, low or moderate levels of TIMP-2 activate pro-MMP-2 while higher levels saturate MT1-MMP and in that way inhibit activation of pro-MMP-2 [50]. Also, it was shown that other MT-MMPs (MT2-MMP, MT3-MMP, MT5-MMP and MT6-MMP) can activate pro-MMP-2 as well [51, 52]. Agents that do not have proteolytic feature, but could activate pro-MMPs, are a thiol group modifying agents oxidized glutathione and reactive oxygen species [53].


Figure 2.

Mutual activation of MMPs.

2.2.2. microRNA and MMP

In the last decade the novelty in the research has emphasized the role of microRNAs (miRNAs) on posttranscriptional regulation of the expression. The number of studies that have focused on this step of MMPs regulation is growing. In this chapter, we will briefly discuss the most recent studies.

Since MMPs have an important role in the progression, metastatic potential and aggressiveness of the cancer, numerous studies have analyzed the MMP regulation by miRNAs in this disease. A recent study has investigated miRNA-489 effect on migration and invasion of hepatocellular carcinoma (HCC) cells. They have found that miRNA-489 overexpression reduced the expressions of MMP7 mRNA and protein. Additionally, miRNA-489 overexpression decreased the luciferase activity of wild type MMP7 3′-UTR but not mutated MMP7 3′-UTR in HEK293T and HCCLM3 cells. The following rescue experiments suggest that miR-489 inhibits the migration and invasion of HCC cells, possibly by targeting MMP7 [54]. Another study has analyzed the functional background of miRNA-204-5p association with better prognosis in patients with melanoma. miRNA-204-5p is down-regulated in melanoma tissues and cells, and confers a protective effect that improves the prognosis of those patients. The binding sites of miRNA-204-5p matched the 3′-UTR of MMP-9. Up-regulation of miRNA-204-5p led to a decrease in the expression of endogenous MMP-9 and their correlation was negative. The authors have demonstrated that MMP-9 is the functional target of miRNA-204-5p in melanoma and concluded that miRNA-204-5p inhibits melanoma growth in vivo by regulating the expression of MMP-9 [55]. Using computational algorithm programs and chromatin immunoprecipitation datasets, Zheng et al. identified neighboring binding sites of myeloid zinc finger 1 (MZF1) and miRNA-337-3p within the MMP-14 promoter. They have found higher MZF1 and MMP-14 levels in gastric cancer cell lines compared to normal gastric epithelial cells. Their research results indicated that miRNA-337-3p significantly decreased the growth, invasion and angiogenesis of gastric cancer cells through repressing MZF1-facilitated MMP-14 expression in vitro, as well as in vivo on animal model [56]. Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers with very poor 5 year survival rate. The research has revealed that miRNA-375 is downregulated in several types of ESCC and that ectopic expression of miRNA-375 suppressed cancer cell aggressiveness in several types of cancer cells. The authors have shown significantly upregulated expression of MMP-13 in 25 ESCC specimens and ESCC cell lines compared with that in 13 normal specimens. They revealed that MMP-13 is directly regulated by antitumor miRNA-375 and acts to regulate several cell cycle promoting genes having the role in the ESCC aggressiveness [57].

With regard to the cardiovascular phenotypes a recent study has investigated miRNA-516a-5p in vascular smooth muscle cells (VSMCs) explant cultured from human abdominal aortic tissues. They have generated stable overexpression and knockdown of miRNA-516a-5p in those VSMCs. The relative MMP-2 protein expression in VSMCs with miRNA-516a-5p-overexpression was significantly higher than that in control VSMCs while the TIMP-1 levels were significantly lower. When miRNA-516a-5p was knockdowned, the opposite results were seen. Additionally, the changes in protein expression of collagen type I alpha 1 chain (COL1A1), TIMP-2 and MMP-9 have not been observed in VSMC. The authors suggested that miRNA-516a-5p may regulate MMP-2 and TIMP-1 expressions in human VSMCs, possibly promoting the proteolytic degradation of elastin for abdominal aortic aneurysm formation. [58]. Another study showed that shear-sensitive miRNA-181b binds to the TIMP-3 3′-UTR and downregulates it when overexpressed in human aortic valve endothelial cells. Additionally, it increases gelatinase/MMP activity. Through specific rescue of TIMP-3, they have clearly shown that the decreased matrix degradation results from anti-miRNA-181b treatment [59]. The miRNA-155 has been considered to be a pro-inflammatory agent, because its major target is the suppressor of cytokine signaling-1(SOCS1). It has been linked to pro-atherogenic processes in humans, as well. A recent study has shown that the SNP in the angiotensin II receptor type 1 AT1R 3′-UTR has significantly changed the miRNA-155 expression in human carotid plaques whereas rare allele homozygotes has a significantly higher expression compared to the subjects carrying wild type allele containing genotypes [60]. Also, miRNA-155 has been reported to participate in cell migration and transformation, but its function in skin wound healing was unknown. Jang et al. have been investigating the function of miRNA-155 on keratinocytes in wound healing. The results of the study showed that the protein level of MMP-2 significantly increased after miRNA-155 overexpression, while the level of TIMP-1 obviously decreased, whereas the levels of MMP-9 and TIMP-2 did not change. The authors concluded that miRNA-155 induced acceleration of keratinocyte migration is mediated at least partly through MMP-2/TIMP-1 pathway in the process of wound healing [61].

2.2.3. Tissue inhibitors of matrix metalloproteinases (TIMPs)

There are a lot of physiological inhibitors of MMPs in the organism. However, in tissues they are primarily regulated by TIMPs that bind MMPs in a 1:1 stoichiometry. Four mammalian TIMPs have been revealed and characterized. They are named TIMP-1, -2, -3 and -4 [6265]. TIMP-1 and -3 are glycoproteins, while TIMP-2 and -4 do not contain carbohydrates. TIMPs inhibit all MMPs but TIMP-1 is a poor inhibitor of three membrane-type MMPs (MT1-MMP, MT3-MMP and MT5-MMP) and MMP-19 [66].

TIMPs have an N-terminal domain of approximately 125 and C-terminal domain of 65 amino acids. Both of these domains contain three conserved disulfide bonds [67, 68]. It is thought that the N-terminal domain is responsible for their binding to MMPs [67]. But there are some exceptions, C-terminal domain of TIMP-1 is shown to bind pro-MMP-9 [69]. Certain TIMPs inhibit different MMPs better than other TIMPs. Additionally, TIMPs do not inhibit only matrixins, several studies have shown that they can inhibit adamalysins as well [70, 71]. It has been shown that expression of TIMP-1 and -3 could be regulated by cytokines and growth factors such as: IL-1, fibroblast growth factor 2, platelet-derived growth factor BB, tumor growth factor-beta and tumor necrosis factor-alpha [72, 73].

TIMPs exert other functions except inhibition of MMPs. For example TIMP-1 and -2 have mitogenic activity for different type of cells [74, 75] and both have antiapoptotic activity [76, 77], while TIMP-3 has proapoptotic activity in tumor cells [78]. Solely, TIMP-2 is shown to have antiangiogenic activity [79].

Several other molecules have been reported to inhibit different MMP-s. The serpine family member, alpha2-macrogobulin, can irreversibly inhibit active MMPs in the circulation [80]. Secreted form of beta-amyloid precursor protein can inhibit MMP-2 [81]. Reversion-inducing cysteine-rich protein with Kazal motif (RECK), a GPI-anchored glycoprotein inhibits MMP-2, MMP-9 and MT1-MMP [82].

3. Synthetic MMP inhibitors

The first efforts in developing synthetic MMPs inhibitors were based on a peptide sequence recognition of the desired MMP and introduction of the group that chelated its catalytic Zn2+ ion. This first generation of the MMP inhibitors was called hydroxamate-based MMP inhibitors. Despite the promising results in animal models regarding their antitumor effects [8385], following clinical studies were unsuccessful [86, 87]. The major concern was unselectivity in MMPs inhibition and serious side effects. It became clear that the knowledge of the MMPs activity in different stages of the disease and spatio-temporal expression needs to be followed in future development of the synthetic inhibitors of MMPs. Nevertheless, although hydroxamate-based MMP inhibitors have not shown the desirable effects the efforts toward their improvement had continued.

The second type of the MMP inhibitors that were developed are non-hydroxamate MMP inhibitors. The hydroxamate was replaced with other Zn2+ binding groups that were more metabolically stable and had higher specificity for MMPs alone. But, again the results were not satisfactory, they all had side effects in different stages of trials. From the other hand, tetracycline antibiotics have an innate ability to inhibit MMPs. The only inhibitor approved by the US Food and Drug Administration for any human disease is collagenase inhibitor doxycycline hyclate, which is a tetracycline analogue [88].

The new approach in synthetic inhibitor development has focused on targeting less conserved sites in MMPs compared to the catalytic one. This should enable more specific targeting and reduce off-target effects that the clinical trials have shown so far. As a result, inhibitors with a much stronger inhibition capacity of target MMPs have been developed [89].

The next alternative strategy has focused on the use of specific antibody fragments. Up to date, functional blocking antibodies that specifically target MT-MMPs have been developed. What is the most important, it seems that antibodies could target specific function of MMP rather than its broad proteolytic activity [90].

Part of the research has investigated the use of endogenous MMP inhibitors as potential therapeutics [91]. Nowadays, it is known that TIMPs have many of non-MMPs functions in the organism and it is very difficult to make them selective and specific to the target MMP inhibition. It could be hard to keep the balance between MMPs and TIMPs which could have serious impact on the overall MMPs activities.

So, there are few important issues to be solved before the efficacious metalloproteinase inhibitors could be made. First of all, there is a need for knowledge of precise MMP functioning and activity in cells, tissues and different stages of the disease. Also, their function in maintaining the tissue and cell homeostasis should be analyzed in details. An additional concern is their overlapping expression patterns and successive activation as well as context-dependent functioning. It seems that they could be good therapeutics for many of diseases, but the designing criteria for synthetic inhibitors are very demanding. We should combine refined and validated experimental and theoretical knowledge in order to raise the selectivity and specificity of the inhibitors toward target MMPs. Another important issue is administration of synthetic MMP inhibitors in order to avoid unnecessary toxicity of the inhibitors in the circulation. It would be of interest to determine the location (cells, tissue and organ) and temporal framework of the adverse MMP activity and develop site-specific delivery systems (detailed review in [92]).

4. MMP genes in human disease

The functions of MMPs are implicated in a variety of diseases, including those of respiratory system, central nervous system, liver, kidneys, muscles, and joints as well as the cardiovascular system [93]. Accordingly, genetic variations in genes that codes for MMPs were investigated in many of them, but only the limited number of genetic variations was thoroughly investigated. Herein, we will review mainly the findings of the genetic influence of MMPs in coronary artery disease (CAD), atherosclerosis and neurodegenerative disease.

4.1. Genetic association of variants in MMPs with vascular disease

Among all the MMPs genes only few were repeatedly investigated in a gene candidate association studies. In the year of 1996 and 1999, the two papers that investigated the functional role of promoter variants in MMP-3 [94] and MMP-9 [95] gene were published, respectively. Since then, the most investigated genetic variants in any of the MMP gene have been the MMP-3 5A/6A (rs3025058) and MMP-9-1562 C/T (rs3918242) variant, based on their role to influence gene transcription.

4.1.1. MMP-3

The common 5A/6A (rs3025058) variant in the promoter of the MMP-3 gene has been shown to affect the level of gene expression in both in vitro [94] and in vivo [96] conditions. The 5A allele was associated with higher and the 6A allele with lower transcriptional activity [94, 96]. In general, the 6A allele was mostly associated with stenosis and coronary disease progression. It was associated with greater progression of coronary artery disease (CAD) in men [97, 98] and women [99] and with the greater number of coronary arteries with significant stenosis [100, 101], but not with susceptibility to coronary heart disease [100, 102]. The 6A/6A genotype was associated with greater progression of coronary atherosclerosis [97] and the number of coronary arteries with stenosis >50% [100]. Also, it was associated with carotid stenosis >70% [103] and greater intima-media thickness (IMT) [103105]. One or more 6A alleles had significantly higher risk for development of carotid atherosclerosis compared to 5A/5A homozygotes [106]. Besides its association with definite cardiovascular phenotypes the 5A/6A polymorphism has been linked to their risk factors such as elevated blood pressure [107], stiffer large arteries [108] and, in combination with angiotensin I-converting enzyme DD genotype, with hypertension in men [109]. On the contrary, the 5A allele as the high activity allele was predominantly associated with acute clinical events such as plaque rupture and consequently myocardial infarction (MI) [100, 110, 111]. The combination of MMP-9 and MMP-3 genotypes was found to be potentially significant for presentation of atherosclerosis. Patients with “high activity genotypes” of both SNPs had larger area of complicated atherosclerotic lesions compared to other genotypes [112]. One of the first meta-analysis that aimed to realize the effect of MMP variants on atherosclerosis found significant effect of the 5A allele on acute MI [113]. The newer meta-analysis of 15 studies (10,061 cases, 8048 controls) in coronary disease displayed no significant overall risk of coronary disease for the carriers of the 5A allele and 6A/6A genotype of rs3025058 [114]. Similarly, the haplotype-tagging approach for several SNPs (rs522616, rs650108, rs569444 and rs635746) and rs3025058 did not show significant difference in genotype distribution in MI patients compared to controls [114]. The meta-analysis of 8 SNPs selected from the studies in which 58 SNPs within MMPs and TIMPs were investigated in abdominal aortic aneurism (AAA) pinpoint the significant association of only MMP-3 rs3025058 with AAA presence [115]. Another one, published the same year, which was investigated several genes in AAA presented the similar results for MMP-3 rs3025058 [116].

4.1.2. MMP-9

The first main role of MMP-9, which gave the rationale for the investigation in aterogenesis is the degradation of basement membrane, which surrounds each VSMC and is primarily composed of type-IV collagen, laminin and fibronectin [117]. The MMP-9 gene possesses several single nucleotide polymorphisms, the most widely studied of which is the −1562 C/T gene polymorphism (rs3918242) in the promoter of the MMP-9 gene [118]. It was suggested that this polymorphism has a functional capacity to regulate MMP-9 expression, since luciferase reporter assays showed higher promoter activity of the T allele in vitro [95]. Although in this study authors have not found the significant effect of the rare allele on the susceptibility to MI they suggested its role in coronary artery severity [95]. Recently, another study challenged the functional role of this SNP [119]. In cells with different −1562C/T genotypes there was neither difference in MMP-9 expression level nor in MMP-9 promoter activity [119]. Nevertheless, this variant was extensively and repeatedly studied in CAD. Both positive [120, 121] and negative [122, 123] association of −1562T allele with the disease were presented. The meta-analysis of previous studies showed no association of MMP-9-1562 C/T polymorphism with coronary heart disease [113]. The other one, which included 11 polymorphisms from MMPs showed that Glu45Lys in MMP3 gene and −1562C/T in MMP9 gene had an overall significant association with CAD [124]. In one of the biggest gene association studies of MMP genes in MI and CAD the composite genotypes of MMP-9 variations CT/RQ had greater risk for MI after full adjustment for covariates [125].

Arterial stiffness and MMP-9 levels were explored in healthy subjects in association with common risk factors and MMP-9 variations. Mean aortic pulse wave velocity (PWV) values were significantly higher in the carriers of the 1562 T and 279 Q alleles compared with common homozygotes, as well as serum MMP-9 levels [126]. The rs3918242 and exon 6 R279Q A/G (rs17576) polymorphisms were not associated with the presence of CAD or MI, but R279Q was associated with hypertension [127]. Among several MMP-2, MMP-7 and MMP-9 variations the MMP-9 R668Q genetic variant was associated with left ventricular dysfunction [128].

In order to overcome a simplistic mechanistic interpretation of the −1562T allele roles in regulation of MMP-9 gene expression, the five promoter and nine exon SNPs, which change amino acid in the encoded protein, were analyzed. The functional consequences of these SNPs were investigated [129]. Three exon SNPs altered the specific enzymatic activity while altered promoter activity was shown for four promoter SNPs among which was the −1562C/T [129]. Still, for promoter SNPs the explanation of how they exert their effect is not known, yet.

Recently, several variants in the 3′ UTR of the MMP-9 gene were analyzed in association with atherosclerotic cerebral infarction (ACI) in Chinese population. They found a significant association of the rare C allele and CC genotype of rs1056628 with ACI. Also the haplotype rs20544C-rs1056628C-rs9509T showed significantly increased risk for ACI. Further findings indicated that miR-491 directly targets MMP-9 and that the A–C transition in rs1056628, which is located in the miR-491 seed sequence, could influence the miR-491 binding. Moreover, the miR-491 decreased MMP-9 protein expression in cotransfected HUVEC, but did not show the influence on the mRNA expression [130].

4.1.3. MMP-2

The other gelatinase, MMP-2, contrary to MMP-9 is constitutively expressed in many of the connective tissue cells that have a role in the vascular system. It is also functionally implicated in the processes of cell invasion, migration of smooth muscle cells (SMC) and destabilization of atherosclerotic plaque. The 15 novel sequence variants in the MMP-2 gene were firstly described in the year of 2001 [131] among which six were in the promoter of the gene and six in the coding region. Among three promoter variants that map onto cis-acting elements the one that disrupts SP-1 type of promoter site (−1306 C/T, rs243865) showed the lower promoter activity in rare allele [131]. The −790 T allele was associated with triple vessel disease [132].

4.1.4. MMP-1

Similarly to other MMP genes the study of MMP-1 genetic variants started with a definition of potentially functional SNPs. First, the 2G-allele of −1607 1G/2G variation in the MMP-1 promoter has been noted to increase transcriptional activity by creating an E26 transcription factor binding site [133]. Next, in vitro analysis in human macrophages showed that the A−519-C−340 and G−519-T−340 haplotypes compared with the A−519-T−340 haplotype, had lower promoter activity, whereas the G−519-C−340 haplotype had greater promoter strength [134]. At the same time that study was one of the first which investigated the genetic variations in MMP-1, solely and in haplotype, in association with cardiovascular disease. It revealed both, risk (G−519-C−340) and protective (A−519-C−340 and G−519-T−340) MMP-1 haplotypes in MI [134]. Recently, the −340 T/C, −519 A/G and −1607 1G/2G variations, separately and in haplotype were associated with the occurrence of carotid plaques (CP). Compared to the referent haplotype 2G−1607-T−340-A−519, the haplotypes 1G−1607-T−34-A−519, 1G−1607-T−340-G−519 and 2G−1607-C−340-A−519 had statistically significant protective effect on CP presence. The MMP-1−1607 2G allele had significantly increased allele dose-dependent risk for CP presence [2]. Previously, the 2G allele also appeared to favor carotid artery stenosis [103].

SNPs in genes encoding MMP-1, -2, -3 and -9 and TIMP-1, -2 and -3 were associated with MI and CAD and combinations of MMP-1 1G/2G and MMP-3 5A/6A genotypes were significantly associated with CAD, but not MI [125]. Recently, the MMP-1/MMP-3 less active haplotype 1G−1607-6A was described as a significant risk factor for obstructive uropathy, which is characterized by collagen accumulation [4]. Others did not find the association of the selected SNPs in MMP1, MMP2, MMP3, MMP9 or MMP10 with either acute MI compared with angina, or with coronary disease compared with controls [135]. Recently, the genome-wide association analysis was performed using 500 K SNPs to identify genes influencing variation in serum levels of MMP-1 [136]. The cluster of 179 SNPs in the cluster on chromosome 11 were associated with MMP-1 serum levels, with the peak of association on rs495366, which is located between the MMP-1 and MMP-3 genes [136].

4.1.5. MMP-8

The investigation of the genetic variations in MMP-8 started with the identification of several polymorphisms in the MMP8 gene, at −799 C/T (rs11225395), −381 A/G (rs1320632) and +17 C/G. Their functional capacity was suggested after the study showed significantly higher promoter activity of the construct that contained the minor alleles compared to the construct with major alleles [137]. Many of the forthcoming studies investigated the role of MMP-8 in atherosclerosis. After analysis of selected 16 SNPs in the MMP-8 gene the rs1940475, in the coding region of the MMP-8 gene, was associated with the extent of coronary atherosclerosis [138]. Also, the minor T allele of rs1940475 was associated with a protective effect against carotid atherosclerosis progression in a 10-year follow-up [138]. In another study the significantly higher frequency of the −381 G allele was found in female patients with carotid atherosclerosis compared to controls [139]. The significantly higher expression of MMP-8 mRNA was found in carotid plaques of the G−381 T−799 haplotype compared to the reference A–381C−799 haplotype [139].

One of the not so commonly investigated MMP gene, the MMP 14, was significantly associated with ultrasonographically defined plaque phenotype suggesting protective effect of rs2236307 major T allele for vulnerable plaque, in Chinese Han population [140].

It seems that a precise definition of particular phenotypes of interest is necessary to get the reproducible findings about genetic influence of a variant in complex disease. The CAD endpoints, the study design as well as a selection of the controls in association studies might influence the findings. The good example of previous is the particular meta-analysis performed for MMP family gene variants [124].

4.1.6. Serum levels of MMPs in atherosclerosis

Over the past 15 years the protein, plasma and serum levels of MMPs were investigated in association with cardiovascular and atherosclerotic plaque phenotypes (mainly MMP-1, MMP-2, MMP-9, MMP-13 and recently MMP-8). MMP-1 but not MMP-9 serum levels were associated with the total plaque burden [141]. Both, MMP-9 and MMP-8 serum and plasma levels were associated with cardiovascular outcomes in CAD patients [142144]. Although MMP-8 cleaves collagen type-I three times more potently than two other interstitial collagenases, MMP-1 and MMP-13 [145], its role in CAD was lesser investigated in comparison to other MMPs, until recently. MMP-8 plasma levels were associated with unstable angina [146] and with the occurrence of carotid plaque [147]. Among the serum levels of MMP-1, -2, -3, -8, -9, -13, and TIMP-1, -2, -3, -4 analyzed prospectively after the MI only the baseline levels of MMP-8 were significantly associated with changes in left ventricular end-diastolic volume after the adjustment for covariates [148].

4.2. Genetics of MMPs in brain disease

In the central nervous system, MMPs have an important role and may influence proteolysis of basement membranes, extracellular matrix molecules, precursors of the cytokines, cell surface molecules and myelin components. In healthy central nervous system (CNS), they also have a role in synaptic plasticity, learning and memory. It is known that MMPs play a significant role in Alzheimer’s disease (AD), Parkinson’s disease (PD) and multiple sclerosis (MS). Their role in neuroinflammation and neurodegeneration was reviewed in detail in Brkic et al. [149]. Thus, as reasonable candidate genes the variations in MMPs were investigated in several neurological diseases.

The results in this field were also partly inconsistent. While one of the first studies that investigated MMP-9 polymorphism in multiple sclerosis had not found that it is a susceptibility marker for MS [150] two other studies showed the significant decrease in the MMP-9 rs3918242 rare T allele carrier ship in female patients with MS [3, 151]. The same allele was found to be more often in patients with PD and amyotrophic lateral sclerosis [152]. The haplotype formed by the −1562 T allele and the L allele ((CA)(<or = 20)) of −90 (CA)n repeat polymorphism in MMP-9 was over-represented in patients with MS in comparison to controls [153]. Others suggested that haplotypes of these two polymorphisms might modulate disease severity, expressed through expanded disability status scale (EDSS) [154]. The MMP-3 6A/6A genotype was also associated with disease severity, showing significantly higher mean multiple sclerosis severity score (MSSS) values in comparison to other genotypes [155]. In another study, the MMP-2 − 1575 G/A variation was shown to influence the age of disease onset in MS patients with optic neuritis as a first symptom [156]. The four polymorphism haplotypes in the gene encoding MMP-3 was associated with changes in amyloid beta levels in non-demented subjects [157] but no evidence was found that the MMP-3gene is causally involved in dementia or AD [158].

4.3. Genetic epilogue

In the last few years the explosion of the data regarding the genetic variations and their association with disease happened as a consequence of the use of high throughput technologies, genome wide association studies, bioinformatical databases, etc. Thus, the results of the candidate gene association studies should be combined with the findings of the different genetic analysis approaches. Some of the genetic variations mentioned above cannot even be found on the arrays, as they are the insertion/deletion variation type, for example, MMP-3 5A/6A or MMP-1 1G/2G. The majority of studies that consider the role of MMPs in different pathologies did not include the genetic component, thus a lot is to be done yet in specifying the genetic architecture of MMPs in health and disease.


1 - Scherer S, de Souza TB, de Paoli J, Brenol CV, Xavier RM, Brenol JC, Chies JA, Simon D. Matrix metalloproteinase gene polymorphisms in patients with rheumatoid arthritis. Rheumatology International. 2010;30:369-373. DOI: 10.1007/s00296-009-0974-8
2 - Djurić T, Stojković L, Zivković M, Končar I, Stanković A, Djordjević A, Alavantić D. Matrix metalloproteinase-1 promoter genotypes and haplotypes are associated with carotid plaque presence. Clinical Biochemistry. 2012;45:1353-1356. DOI: 10.1016/j.clinbiochem.2012.05.032
3 - Zivković M, Djurić T, Dincić E, Raicević R, Alavantić D, Stanković A. Matrix metalloproteinase-9 −1562 C/T gene polymorphism in Serbian patients with multiple sclerosis. Journal of Neuroimmunology. 2007;189:147-150. DOI: 10.1016/j.jneuroim.2007.06.022
4 - Djuric T, Zivkovic M, Milosevic B, Andjelevski M, Cvetkovic M, Kostic M, Stankovic A. MMP-1 and -3 haplotype is associated with congenital anomalies of the kidney and urinary tract. Pediatric Nephrology. 2014;29:879-884. DOI: 10.1007/s00467-013-2699-x
5 - Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nature Reviews. Cancer. 2002;2:161-174. DOI: 10.1038/nrc745
6 - Pendas AM, Santamaria I, Alvarez MV, Pritchard M, Lopez-Otin C. Fine physical mapping of the human matrix metalloproteinase genes clustered on chromosome 11q22.3. Genomics. 1996;37:266-268. DOI: 10.1006/geno.1996.0557
7 - Sterchi EE. Special issue: metzincin metalloproteinases. Molecular Aspects of Medicine. 2008;29:255-257. DOI: 10.1016/j.mam.2008.08.007
8 - Murphy G, Nagase H. Progress in matrix metalloproteinase research. Molecular Aspects of Medicine. 2008;29:290-308. DOI: 10.1016/j.mam.2008.05.002
9 - Iyer RP, Patterson NL, Fields GB, Lindsey ML. The history of matrix metalloproteinases: Milestones, myths, and misperceptions. American Journal of Physiology. Heart and Circulatory Physiology. 2012;303:H919-H930. DOI: 10.1152/ajpheart.00577.2012
10 - Van Wart HE, Birkedal-Hansen H. The cysteine switch: A principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proceedings of the National Academy of Sciences of the United States of America. 1990;87:5578-5582
11 - Ra HJ, Parks WC. Control of matrix metalloproteinase catalytic activity. Matrix Biology. 2007;26:587-596. DOI: 10.1016/j.matbio.2007.07.001
12 - Bode W, Gomis-Rüth FX, Stöckler W. Astacins, serralysins, snake venom and matrix metalloproteinases exhibit identical zinc-binding environments (HEXXHXXGXXH and met-turn) and topologies and should be grouped into a common family, the ‘metzincins’. FEBS Letters. 1993;331:134-140. DOI: 10.1016/0014-5793(93)80312-I
13 - Aimes RT, Quigley JP. Matrix metalloproteinase-2 is an interstitial collagenase. Inhibitor-free enzyme catalyzes the cleavage of collagen fibrils and soluble native type I collagen generating the specific 3/4- and 1/4-length fragments. The Journal of Biological Chemistry. 1995;270:5872-5876. DOI: 10.1074/jbc.270.11.5872
14 - Patterson ML, Atkinson SJ, Knäuper V, Murphy G. Specific collagenolysis by gelatinase a, MMP-2, is determined by the hemopexin domain and not the fibronectin-like domain. FEBS Letters. 2001;503:158-162. DOI: 10.1016/S0014-5793(01)02723-5
15 - Suzuki K, Enghild JJ, Morodomi T, Salvesen G, Nagase H. Mechanisms of activation of tissue procollagenase by matrix metalloproteinase 3 (stromelysin). Biochemistry. 1990;29:10261-10270
16 - English WR, Holtz B, Vogt G, Knäuper V, Murphy G. Characterization of the role of the “MT-loop”: An eight-amino acid insertion specific to progelatinase A (MMP2) activating membrane-type matrix metalloproteinases. The Journal of Biological Chemistry. 2001;276:42018-42026. DOI: 10.1074/jbc.M107783200
17 - Ohuchi E, Imai K, Fujii Y, Sato H, Seiki M, Okada Y. Membrane type1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. The Journal of Biological Chemistry. 1997;272:2446-2451. DOI: 10.1074/jbc.272.4.2446
18 - Knäuper V, Will H, López-Otin C, Smith B, Atkinson SJ, Stanton H, Hembry RM, Murphy G. Cellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase a (MMP-2) are able to generate active enzyme. The Journal of Biological Chemistry. 1996;271:17124-17131. DOI: 10.1074/jbc.271.29.17124
19 - Shapiro SD, Kobayashi DK, Ley TJ. Cloning and characterization of a unique elastolytic metalloproteinase produced by human alveolar macrophages. The Journal of Biological Chemistry. 1993;268:23824-23829
20 - Kerkelä E, Bohling T, Herva R, Uria JA, Saarialho-Kere U. Human macrophage metalloelastase (MMP-12) expression is induced in chondrocytes during fetal development and malignant transformation. Bone. 2001;29:487-493
21 - Hou P, Troen T, Ovejero MC, Kirkegaard T, Andersen TL, Byrjalsen I, Ferreras M, Sato T, Shapiro SD, Foged NT, Delaisse JM. Matrix metalloproteinase-12 (MMP-12) in osteoclasts: New lesson on the involvement of MMPs in bone resorption. Bone. 2004;34:37-47
22 - Shipley JM, Wesselschmidt RL, Kobayashi DK, Ley TJ, Shapiro SD. Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. Proceedings of the National Academy of Sciences of the United States of America. 1996;93:3942-3946
23 - Pendas AM, Knäuper V, Puente XS, Llano E, Mattei MG, Apte S, Murphy G, López-Otín C. Identification and characterization of a novel human matrix metalloproteinase with unique structural characteristics, chromosomal location, and tissue distribution. The Journal of Biological Chemistry. 1997;272:4281-4286. DOI: 10.1074/jbc.272.7.4281
24 - Stracke JO, Hutton M, Stewart M, Pendas AM, Smith B, Lopez-Otin C, Murphy G, Knauper V. Biochemical characterization of the catalytic domain of human matrix metalloproteinase 19—Evidence for a role as a potent basement membrane degrading enzyme. The Journal of Biological Chemistry. 2000;275:14809-14816
25 - Sadowski T, Dietrich S, Koschinsky F, Ludwig A, Proksch E, Titz B, Sedlacek R. Matrix metalloproteinase 19 processes the laminin 5 gamma 2 chain and induces epithelial cell migration. Cellular and Molecular Life Sciences. 2005;62:870-880. DOI: 10.1007/s00018-005-4478-8
26 - Ryu OH, Fincham AG, Hu CC, Zhang C, Qian Q, Bartlett JD, Simmer JP. Characterization of recombinant pig enamelysin activity and cleavage of recombinant pig and mouse amelogenins. Journal of Dental Research. 1999;78:743-750
27 - Li W, Gibson CW, Abrams WR, Andrews DW, DenBesten PK. Reduced hydrolysis of amelogenin may result in X-linked amelogenesis imperfecta. Matrix Biology. 2001;19:755-760. DOI: 10.1016/S0945-053X(00)00121-9
28 - Ahokas K, Lohi J, Illman SA, Llano E, Elomaa O, Impola U, Karjalainen-Lindsberg ML, Saarialho-Kere U. Matrix metalloproteinase-21 is expressed epithelially during development and in cancer and is up-regulated by transforming growth factor-beta1 in keratinocytes. Laboratory Investigation. 2003;83:1887-1899. DOI: 10.1097/01.LAB.0000106721.86126.39
29 - Velasco G, Pendás AM, Fueyo A, Knäuper V, Murphy G, López-Otín C. Cloning and characterization of human MMP-23, a new matrix metalloproteinase predominantly expressed in reproductive tissues and lacking conserved domains in other family members. The Journal of Biological Chemistry. 1999;274:4570-4576. DOI: 10.1074/jbc.274.8.4570
30 - Bar-Or A, Nuttall RK, Duddy M, Alter A, Kim HJ, Ifergan I, Pennington CJ, Bourgoin P, Edwards DR, Yong VW. Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis. Brain. 2003;126:2738-2749. DOI: 10.1093/brain/awg285
31 - Lohi J, Wilson CL, Roby JD, Parks WC. Epilysin, a novel human matrix metalloproteinase (MMP-28) expressed in testis and keratinocytes and in response to injury. The Journal of Biological Chemistry. 2001;276:10134-10144. DOI: 10.1074/jbc.M001599200
32 - Saarialho-Kere U, Kerkelä E, Jahkola T, Suomela S, Keski-Oja J, Lohi J. Epilysin (MMP-28) expression is associated with cell proliferation during epithelial repair. The Journal of Investigative Dermatology. 2002;119:14-21. DOI: 10.1046/j.1523-1747.2002.01790.x
33 - Kevorkian L, Young DA, Darrah C, Donell ST, Shepstone L, Porter S, Brockbank SM, Edwards DR, Parker AE, Clark IM. Expression profiling of metalloproteinases and their inhibitors in cartilage. Arthritis and Rheumatism. 2004;50:131-141. DOI: 10.1002/art.11433
34 - Momohara S, Okamoto H, Komiya K, Ikari K, Takeuchi M, Tomatsu T, Kamatani N. Matrix metalloproteinase 28/epilysin expression in cartilage from patients with rheumatoid arthritis and osteoarthritis: Comment on the article by Kevorkian et al. Arthritis and Rheumatism. 2004;50:4074-4075; author reply 4075. DOI: 10.1002/art.20799
35 - Illman SA, Lehti K, Keski-Oja J, Lohi J. Epilysin (MMP-28) induces TGF-beta mediated epithelial to mesenchymal transition in lung carcinoma cells. Journal of Cell Science. 2006;119:3856-3865. DOI: 10.1242/jcs.03157
36 - Kim DH, Sætrom P, Snøve O, Rossi JJ. MicroRNA-directed transcriptional gene silencing in mammalian cells. Proceedings of the National Academy of Sciences of the United States of America. 2008;105:16230-16235. DOI: 10.1073/pnas.0808830105
37 - Younger ST, Corey DR. Transcriptional gene silencing in mammalian cells by miRNA mimics that target gene promoters. Nucleic Acids Research. 2011;39:5682-5691. DOI: 10.1093/nar/gkr155
38 - Johnson JL. Matrix metalloproteinases: Influence on smooth muscle cells and atherosclerotic plaque stability. Expert Review of Cardiovascular Therapy. 2007;5:265-282. DOI: 10.1586/14779072.5.2.265
39 - Nagase H, Woessner JF Jr. Matrix metalloproteinases. The Journal of Biological Chemistry. 1999;274:21491-21494. DOI: 10.1074/jbc.274.31.21491
40 - Ye S. Influence of matrix metalloproteinase genotype on cardiovascular disease susceptibility and outcome. Cardiovascular Research. 2006;69:636-645. DOI: 10.1016/j.cardiores.2005.07.015
41 - Nagase H. Activation mechanisms of matrix metalloproteinases. Biological Chemistry. 1997;378:151-160
42 - Sato H, Kinoshita T, Takino T, Nakayama K, Seiki M. Activation of a recombinant membrane type 1-matrix metalloproteinase (MT1-MMP) by furin and its interaction with tissue inhibitor of metalloproteinases (TIMP)-2. FEBS Letters. 1996;393:101-104. DOI: 10.1016/0014-5793(96)00861-7
43 - Wang X, Pei D. Shedding of membrane type matrix metalloproteinase 5 by a furin-type convertase: A potential mechanism for down-regulation. The Journal of Biological Chemistry. 2001;276:35953-35960. DOI: 10.1074/jbc.M103680200
44 - Kang T, Nagase H, Pei D. Activation of membrane-type matrix metalloproteinase 3 zymogen by the proprotein convertase furin in the trans-Golgi network. Cancer Research. 2002;62:675-681
45 - Pei D, Weiss SJ. Furin-dependent intracellular activation of the human stromelysin-3 zymogen. Nature. 1995;375:244-247. DOI: 10.1038/375244a0
46 - Lijnen HR. Plasmin and matrix metalloproteinases in vascular remodeling. Thrombosis and Haemostasis. 2001;86:324-333
47 - Gruber BL, Marchese MJ, Suzuki K, Schwartz LB, Okada Y, Nagase H, Ramamurthy NS. Synovial procollagenase activation by human mast cell tryptase dependence upon matrix metalloproteinase 3 activation. The Journal of Clinical Investigation. 1989;84:1657-1662. DOI: 10.1172/JCI114344
48 - Johnson JL, Jackson CL, Angelini GD, George SJ. Activation of matrix-degrading metalloproteinases by mast cell proteases in atherosclerotic plaques. Arteriosclerosis, Thrombosis, and Vascular Biology. 1998;18:1707-1715. DOI: 10.1161/01.ATV.18.11.1707
49 - Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E, Seiki M. A matrix metalloproteinase expressed on the surface of invasive tumor cells. Nature. 1994;370:61-65
50 - Strongin AY, Collier I, Bannikov G, Marmer BL, Grant GA, Goldberg GI. Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. The Journal of Biological Chemistry. 1995;270:5331-5338. DOI: 10.1074/jbc.270.10.5331
51 - Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: Structure, function, and biochemistry. Circulation Research. 2003;92:827-839. DOI: 10.1161/01.RES.0000070112.80711.3D
52 - Nie J, Pei D. Direct activation of pro-matrix metalloproteinase-2 by leukolysin/membrane-type 6 matrix metalloproteinase/matrix metalloproteinase 25 at the asn(109)-Tyr bond. Cancer Research. 2003;63:6758-6762
53 - Nelson KK, Melendez JA. Mitochondrial redox control of matrix metalloproteinases. Free Radical Biology & Medicine. 2004;37:768-784. DOI: 10.1016/j.freeradbiomed.2004.06.008
54 - Lin Y, Liu J, Huang Y, Liu D, Zhang G, Kan H. microRNA-489 plays an anti-metastatic role in human hepatocellular carcinoma by targeting matrix metalloproteinase-7. Translational Oncology. 2017;10:211-220. DOI: 10.1016/j.tranon.2017.01.010
55 - Luan W, Qian Y, Ni X, Bu X, Xia Y, Wang J, Ruan H, Ma S, Xu B. miR-204-5p acts as a tumor suppressor by targeting matrix metalloproteinases-9 and B-cell lymphoma-2 in malignant melanoma. OncoTargets and Therapy. 2017;10:1237-1246. DOI: 10.2147/OTT.S128819
56 - Zheng L, Jiao W, Mei H, Song H, Li D, Xiang X, Chen Y, Yang F, Li H, Huang K, Tong Q. miRNA-337-3p inhibits gastric cancer progression through repressing myeloid zinc finger 1-facilitated expression of matrix metalloproteinase 14. Oncotarget. 2016;7:40314-40328. DOI: 10.18632/oncotarget.9739
57 - Osako Y, Seki N, Kita Y, Yonemori K, Koshizuka K, Kurozumi A, Omoto I, Sasaki K, Uchikado Y, Kurahara H, Maemura K, Natsugoe S. Regulation of MMP13 by antitumor microRNA-375 markedly inhibits cancer cell migration and invasion in esophageal squamous cell carcinoma. International Journal of Oncology. 2016;49:2255-2264. DOI: 10.3892/ijo.2016.3745
58 - Chan CY, Cheuk BL, Cheng SW. Abdominal aortic aneurysm-associated microRNA-516a-5p regulates expressions of methylenetetrahydrofolate reductase, matrix metalloproteinase-2, and tissue inhibitor of matrix metalloproteinase-1 in human abdominal aortic vascular smooth muscle cells. Annals of Vascular Surgery. 2017;42:263-273.DOI: 10.1016/j.avsg.2016.10.062
59 - Heath JM, Fernandez Esmerats J, Khambouneheuang L, Kumar S, Simmons R, Jo H. Mechanosensitive microRNA-181b regulates aortic valve endothelial matrix degradation by targeting TIMP3. Cardiovascular Engineering and Technology. 2017. DOI: 10.1007/s13239-017-0296-z
60 - Stanković A, Kolaković A, Živković M, Djurić T, Bundalo M, Končar I, Davidović L, Alavantić D. Angiotensin receptor type 1 polymorphism A1166C is associated with altered AT1R and miR-155 expression in carotid plaque tissue and development of hypoechoic carotid plaques. Atherosclerosis. 2016;248:132-9. DOI: 10.1016/j.atherosclerosis.2016.02.032
61 - Yang L, Zheng Z, Zhou Q, Bai X, Fan L, Yang C, Su L, Hu D. miR-155 promotes cutaneous wound healing through enhanced keratinocytes migration by MMP-2. Journal of Molecular Histology. 2017;48:147-155. DOI: 10.1007/s10735-017-9713-8
62 - Carmichael DF, Sommer A, Thompson RC, Anderson DC, Smith CG, Welgus HG, Stricklin GP. Primary structure and cDNA cloning of human fibroblast collagenase inhibitor. Proceedings of the National Academy of Sciences of the United States of America. 1986;83:2407-2411
63 - Stetler-Stevenson WG, Krutzsch HC, Liotta LA. Tissue inhibitor of metalloproteinase (TIMP-2). A new member of the metalloproteinase inhibitor family. The Journal of Biological Chemistry. 1989;264:17374-17378
64 - Wick M, Bürger C, Brüsselbach S, Lucibello FC, Müller R. A novel member of human tissue inhibitor of metalloproteinases (TIMP) gene family is regulated during G1 progression, mitogenic stimulation, differentiation, and senescence. The Journal of Biological Chemistry. 1994;269:18953-18960
65 - Greene J, Wang M, Liu YE, Raymond LA, Rosen C, Shi YE. Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4. The Journal of Biological Chemistry. 1996;271:30375-30380. DOI: 10.1074/jbc.271.48.30375
66 - Baker AH, Edwards DR, Murphy G. Metalloproteinase inhibitors: Biological actions and therapeutic opportunities. Journal of Cell Science. 2002;115:3719-3727. DOI: 10.1242/jcs.00063
67 - Murphy G, Houbrechts A, Cockett MI, Williamson RA, O’Shea M, Docherty AJ. The N-terminal domain of tissue inhibitor of metalloproteinases retains metalloproteinase inhibitory activity. Biochemistry. 1991;30:8097-8102
68 - Williamson RA, Marston FA, Angal S, Koklitis P, Panico M, Morris HR, Carne AF, Smith BJ, Harris TJ, Freedman RB. Disulfide bondassignment in human tissue inhibitor of metalloproteinases (TIMP). The Biochemical Journal. 1990;268:267-274
69 - Fassina G, Ferrari N, Brigati C, Benelli R, Santi L, Noonan DM, Albini A. Tissue inhibitors of metalloproteases: Regulation and biological activities. Clinical & Experimental Metastasis. 2000;18:111-120
70 - Wang WM, Ge G, Lim NH, Nagase H, Greenspan DS. TIMP-3 inhibits the procollagen N-proteinase ADAMTS-2. The Biochemical Journal. 2006;398:515-519. DOI: 10.1042/BJ20060630
71 - Jacobsen J, Visse R, Sørensen HP, Enghild JJ, Brew K, Wewer UM, Nagase H. Catalytic properties of ADAM12 and its domain deletion mutants. Biochemistry. 2008;47:537-547. DOI: 10.1021/bi701629c
72 - Fabunmi RP, Baker AH, Murray EJ, Booth RF, Newby AC. Divergent regulation by growth factors and cytokines of 95 kDa and 72 kDa gelatinases and tissue inhibitors or metalloproteinases-1, -2, and -3 in rabbit aortic smooth muscle cells. The Biochemical Journal. 1996;315:335-342
73 - Overall CM. Regulation of tissue inhibitor of matrix metalloproteinase expression. Annals of the New York Academy of Sciences. 1994;732:51-64. DOI: 10.1111/j.1749-6632.1994.tb24724.x
74 - Hayakawa T, Yamashita K, Tanzawa K, Uchijima E, Iwata K. Growth-promoting activity of tissue inhibitor of metalloproteinases-1 (TIMP-1) for a wide range of cells. A possible new growth factor in serum. FEBS Letters. 1992;298:29-32. DOI: 10.1016/0014-5793(92)80015-9
75 - Hayakawa T, Yamashita K, Ohuchi E, Shinagawa A. Cell growth-promoting activity of tissue inhibitor of metalloproteinases-2 (TIMP-2). Journal of Cell Science. 1994;107:2373-2379
76 - Guedez L, Courtemanch L, Stetler-Stevenson M. Tissue inhibitor of metalloproteinase (TIMP)-1 induces differentiation and an antiapoptotic phenotype in germinal center B cells. Blood. 1998;92:1342-1349
77 - Valente P, Fassina G, Melchiori A, Masiello L, Cilli M, Vacca A, Onisto M, Santi L, Stetler-Stevenson WG, Albini A. TIMP-2 over-expression reduces invasion and angiogenesis and protects B16F10 melanoma cells from apoptosis. International Journal of Cancer. 1998;75:246-253. DOI: 10.1002/(SICI)1097-0215(19980119)75:2<246::AID-IJC13>3.0.CO;2-B
78 - Ahonen M, Poukkula M, Baker AH, Kashiwagi M, Nagase H, Eriksson JE, Kähäri VM. Tissue inhibitor of metalloproteinases-3 induces apoptosis in melanoma cells by stabilization of death receptors. Oncogene. 2003;22:2121-2134. DOI: 10.1038/sj.onc.1206292
79 - Murphy AN, Unsworth EJ, Stetler-Stevenson WG. Tissue inhibitor of metalloproteinases-2 inhibits bFGF-induced human microvascular endothelial cell proliferation. Journal of Cellular Physiology. 1993;157:351-358. DOI: 10.1002/jcp.1041570219
80 - Borth W. Alpha 2-macroglobulin, a multifunctional binding protein with targeting characteristics. The FASEB Journal. 1992;6:3345-3353
81 - Higashi S, Miyazaki K. Novel processing of beta-amyloid precursor protein catalyzed by membrane type 1 matrix metalloproteinase releases a fragment lacking the inhibitor domain against gelatinase A. Biochemistry. 2003;42:6514-6526. DOI: 10.1021/bi020643m
82 - Oh J, Takahashi R, Kondo S, Mizoguchi A, Adachi E, Sasahara RM, Nishimura S, Imamura Y, Kitayama H, Alexander DB, Ide C, Horan TP, Arakawa T, Yoshida H, Nishikawa S, Itoh Y, Seiki M, Itohara S, Takahashi C, Noda M. The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell. 2001;107:789-800. DOI: 10.1016/S0092-8674(01)00597-9
83 - Sledge GW Jr, Qulali M, Goulet R, Bone EA, Fife R. Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. Journal of the National Cancer Institute. 1995;87:1546-1450
84 - Low JA, Johnson MD, Bone EA, Dickson RB. The matrix metalloproteinase inhibitor batimastat (BB-94) retards human breast cancer solid tumor growth but not ascites formation in nude mice. Clinical Cancer Research. 1996;2:1207-1214
85 - Watson SA, Morris TM, Robinson G, Crimmin MJ, Brown PD, Hardcastle JD. Inhibition of organ invasion by the matrix metalloproteinase inhibitor batimastat (BB-94) in two human colon carcinoma metastasis models. Cancer Research. 1995;55:3629-3633
86 - Rao BG. Recent developments in the design of specific matrix metalloproteinase inhibitors aided by structural and computational studies. Current Pharmaceutical Design. 2005;11:295-322
87 - Mannello F, Tonti G, Papa S. Matrix metalloproteinase inhibitors as anticancer therapeutics. Current Cancer Drug Targets. 2005;5:285-298
88 - Sorsa T, Tjäderhane L, Konttinen YT, Lauhio A, Salo T, Lee HM, Golub LM, Brown DL, Mäntylä P. Matrix metalloproteinases: Contribution to pathogenesis, diagnosis and treatment of periodontal inflammation. Annals of Medicine. 2006;38:306-321. DOI: 10.1080/07853890600800103
89 - Overall CM, Kleifeld O. Toward third generation matrix metalloproteinase inhibitors for cancer therapy. British Journal of Cancer. 2006;94:941-946. DOI: 10.1038/sj.bjc.6603043
90 - Shiryaev SA, Remacle AG, Golubkov VS, Ingvarsen S, Porse A, Behrendt N, Cieplak P, Strongin AY. A monoclonal antibody interferes with TIMP-2 binding and incapacitates the MMP-2-activating function of multifunctional, pro-tumorigenic MMP-14/MT1-MMP. Oncogene. 2013;2:e80. DOI: 10.1038/oncsis.2013.44
91 - Murphy G. Tissue inhibitors of metalloproteinases. Genome Biology. 2011;12:233. DOI: 10.1186/gb-2011-12-11-233
92 - Vandenbroucke RE, Libert C. Is there new hope for therapeutic matrix metalloproteinase inhibition? Nature Reviews. Drug Discovery. 2014;13:904-927. DOI: 10.1038/nrd4390
93 - Shiomi T, Lemaitre V, D'Armiento J, Okada Y. Matrix metalloproteinases, a disintegrin and metalloproteinases, and a disintegrin and metalloproteinases with thrombospondin motifs in non-neoplastic diseases. Pathology International. 2010;60:477-496. DOI: 10.1111/j.1440-1827.2010.02547.x
94 - 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. The Journal of Biological Chemistry. 1996;271:13055-13060
95 - Zhang B, Ye S, Herrmann SM, Eriksson P, de Maat M, Evans A, et al. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation. 1999;99:1788-1794
96 - Zhu C, Odeberg J, Hamsten A, Eriksson P. Allele-specific MMP-3 transcription under in vivo conditions. Biochemical and Biophysical Research Communications. 2006;348:1150-1156. DOI: 10.1016/j.bbrc.2006.07.174
97 - Ye S, Watts GF, Mandalia S, Humphries SE, Henney AM. Preliminary report: Genetic variation in the human stromelysin promoter is associated with progression of coronary atherosclerosis. British Heart Journal. 1995;73:209-215
98 - Humphries SE, Luong LA, Talmud PJ, Frick MH, Kesaniemi YA, Pasternack A, et al. The 5A/6A polymorphism in the promoter of the stromelysin-1 (MMP-3) gene predicts progression of angiographically determined coronary artery disease in men in the LOCAT gemfibrozil study. Lopid coronary angiography trial. Atherosclerosis. 1998;139:49-56
99 - Hirashiki A, Yamada Y, Murase Y, Suzuki Y, Kataoka H, Morimoto Y, et al. Association of gene polymorphisms with coronary artery disease in low- or high-risk subjects defined by conventional risk factors. Journal of the American College of Cardiology. 2003;42:1429-1437
100 - Beyzade S, Zhang S, Wong YK, Day IN, Eriksson P, Ye S. Influences of matrix metalloproteinase-3 gene variation on extent of coronary atherosclerosis and risk of myocardial infarction. Journal of the American College of Cardiology. 2003;41:2130-2137
101 - Schwarz A, Haberbosch W, Tillmanns H, Gardemann A. The stromelysin-1 5A/6A promoter polymorphism is a disease marker for the extent of coronary heart disease. Disease Markers. 2002;18:121-128
102 - Ye S, Gale CR, Martyn CN. Variation in the matrix metalloproteinase-1 gene and risk of coronary heart disease. European Heart Journal. 2003;24:1668-1671
103 - Ghilardi G, Biondi ML, DeMonti M, Turri O, Guagnellini E, Scorza R. Matrix metalloproteinase-1 and matrix metalloproteinase-3 gene promoter polymorphisms are associated with carotid artery stenosis. Stroke. 2002;33:2408-2412
104 - Rauramaa R, Vaisanen SB, Luong LA, Schmidt-Trucksass A, Penttila IM, Bouchard C, et al. Stromelysin-1 and interleukin-6 gene promoter polymorphisms are determinants of asymptomatic carotid artery atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:2657-2662
105 - Rundek T, Elkind MS, Pittman J, Boden-Albala B, Martin S, Humphries SE, et al. Carotid intima-media thickness is associated with allelic variants of stromelysin-1, interleukin-6, and hepatic lipase genes: The Northern Manhattan prospective cohort study. Stroke. 2002;33:1420-1423
106 - Djuric T, Zivkovic M, Radak D, Jekic D, Radak S, Stojkovic L, et al. Association of MMP-3 5A/6A gene polymorphism with susceptibility to carotid atherosclerosis. Clinical Biochemistry. 2008;41:1326-1329. DOI: 10.1016/j.clinbiochem.2008.08.081
107 - Beilby JP, Chapman CM, Palmer LJ, McQuillan BM, Thompson PL, Hung J. Stromelysin-1 (MMP-3) gene 5A/6A promoter polymorphism is associated with blood pressure in a community population. Journal of Hypertension. 2005;23:537-542
108 - Medley TL, Kingwell BA, Gatzka CD, Pillay P, Cole TJ. Matrix metalloproteinase-3 genotype contributes to age-related aortic stiffening through modulation of gene and protein expression. Circulation Research. 2003;92:1254-1261. DOI: 10.1161/
109 - Zivkovic M, Djuric T, Alavantic D, Mecanin S, Stankovic A. Association of ACE I/D and MMP-3 5A/6A gene polymorphisms with hypertension in Serbian males. Archives of Biological Sciences. 2006;58:205-210
110 - Terashima M, Akita H, Kanazawa K, Inoue N, Yamada S, Ito K, et al. Stromelysin promoter 5A/6A polymorphism is associated with acute myocardial infarction. Circulation. 1999;99:2717-2719
111 - Nojiri T, Morita H, Imai Y, Maemura K, Ohno M, Ogasawara K, et al. Genetic variations of matrix metalloproteinase-1 and -3 promoter regions and their associations with susceptibility to myocardial infarction in Japanese. International Journal of Cardiology. 2003;92:181-186
112 - Pollanen PJ, Lehtimaki T, Mikkelsson J, Ilveskoski E, Kunnas T, Perola M, et al. Matrix metalloproteinase3 and 9 gene promoter polymorphisms: Joint action of two loci as a risk factor for coronary artery complicated plaques. Atherosclerosis. 2005;180:73-78. DOI: 10.1016/j.atherosclerosis.2004.10.041
113 - Abilleira S, Bevan S, Markus HS. The role of genetic variants of matrix metalloproteinases in coronary and carotid atherosclerosis. Journal of Medical Genetics. 2006;43:897-901. DOI: 10.1136/jmg.2006.040808
114 - Koch W, de Waha A, Hoppmann P, Schomig A, Kastrati A. Haplotypes and 5A/6A polymorphism of the matrix metalloproteinase-3 gene in coronary disease: Case–control study and a meta-analysis. Atherosclerosis. 2010;208:171-176. DOI: 10.1016/j.atherosclerosis.2009.08.021
115 - Morris DR, Biros E, Cronin O, Kuivaniemi H, Golledge J. The association of genetic variants of matrix metalloproteinases with abdominal aortic aneurysm: A systematic review and meta-analysis. Heart. 2014;100:295-302. DOI: 10.1136/heartjnl-2013-304129
116 - Saratzis A, Bown MJ, Wild B, Nightingale P, Smith J, Johnson C, et al. Association between seven single nucleotide polymorphisms involved in inflammation and proteolysis and abdominal aortic aneurysm. Journal of Vascular Surgery. 2015;61:1120-1128 e1121. DOI: 10.1016/j.jvs.2013.11.099
117 - Newby AC, Zaltsman AB. Fibrous cap formation or destruction--the critical importance of vascular smooth muscle cell proliferation, migration and matrix formation. Cardiovascular Research. 1999;41:345-360
118 - Zhang B, Henney A, Eriksson P, Hamsten A, Watkins H, Ye S. Genetic variation at the matrix metalloproteinase-9 locus on chromosome 20q12.2-13.1. Human Genetics. 1999;105:418-423
119 - Maqbool A, Turner NA, Galloway S, Riches K, O'Regan DJ, Porter KE. The -1562C/T MMP-9 promoter polymorphism does not predict MMP-9 expression levels or invasive capacity in saphenous vein smooth muscle cells cultured from different patients. Atherosclerosis. 2009;207:458-465. DOI: 10.1016/j.atherosclerosis.2009.05.028
120 - Morgan AR, Zhang B, Tapper W, Collins A, Ye S. Haplotypic analysis of the MMP-9 gene in relation to coronary artery disease. Journal of Molecular Medicine (Berlin). 2003;81:321-326. DOI: 10.1007/s00109-003-0441-z
121 - Cho HJ, Chae IH, Park KW, Ju JR, Oh S, Lee MM, et al. Functional polymorphism in the promoter region of the gelatinase B gene in relation to coronary artery disease and restenosis after percutaneous coronary intervention. Journal of Human Genetics. 2002;47:88-91. DOI: 10.1007/s100380200006
122 - Wang J, Warzecha D, Wilcken D, Wang XL. Polymorphism in the gelatinase B gene and the severity of coronary arterial stenosis. Clinical Science (London, England). 2001;101:87-92
123 - Haberbosch W, Gardemann A. Gelatinase B C(−1562)T polymorphism in relation to ischaemic heart disease. Scandinavian Journal of Clinical and Laboratory Investigation. 2005;65:513-522. DOI: 10.1080/00365510500206575
124 - Niu W, Qi Y. Matrix metalloproteinase family gene polymorphisms and risk for coronary artery disease: Systematic review and meta-analysis. Heart. 2012;98:1483-1491. DOI: 10.1136/heartjnl-2012-302085
125 - Horne BD, Camp NJ, Carlquist JF, Muhlestein JB, Kolek MJ, Nicholas ZP, et al. Multiple-polymorphism associations of 7 matrix metalloproteinase and tissue inhibitor metalloproteinase genes with myocardial infarction and angiographic coronary artery disease. American Heart Journal. 2007;154:751-758. DOI: 10.1016/j.ahj.2007.06.030
126 - Yasmin, McEniery CM, O'Shaughnessy KM, Harnett P, Arshad A, Wallace S, et al. Variation in the human matrix metalloproteinase-9 gene is associated with arterial stiffness in healthy individuals. Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1799-1805. DOI: 10.1161/01.atv.0000227717.46157.32
127 - Opstad TB, Pettersen AA, Weiss TW, Akra S, Ovstebo R, Arnesen H, et al. Genetic variation, gene-expression and circulating levels of matrix metalloproteinase-9 in patients with stable coronary artery disease. Clinica Chimica Acta. 2012;413:113-120. DOI: 10.1016/j.cca.2011.09.004
128 - Mishra A, Srivastava A, Mittal T, Garg N, Mittal B. Association of matrix metalloproteinases (MMP2, MMP7 and MMP9) genetic variants with left ventricular dysfunction in coronary artery disease patients. Clinica Chimica Acta. 2012;413:1668-1674. DOI: 10.1016/j.cca.2012.05.012
129 - Duellman T, Warren CL, Peissig P, Wynn M, Yang J. Matrix metalloproteinase-9 genotype as a potential genetic marker for abdominal aortic aneurysm. Circulation. Cardiovascular Genetics. 2012;5:529-537. DOI: 10.1161/circgenetics.112.963082
130 - Yuan M, Zhan Q, Duan X, Song B, Zeng S, Chen X, et al. A functional polymorphism at miR-491-5p binding site in the 3′-UTR of MMP-9 gene confers increased risk for atherosclerotic cerebral infarction in a Chinese population. Atherosclerosis. 2013;226:447-452. DOI: 10.1016/j.atherosclerosis.2012.11.026
131 - Price SJ, Greaves DR, Watkins H. Identification of novel, functional genetic variants in the human matrix metalloproteinase-2 gene: Role of Sp1 in allele-specific transcriptional regulation. The Journal of Biological Chemistry. 2001;276:7549-7558. DOI: 10.1074/jbc.M010242200
132 - Vasku A, Goldbergova M, Izakovicova Holla L, Siskova L, Groch L, Beranek M, et al. A haplotype constituted of four MMP-2 promoter polymorphisms (−1575G/a, −1306C/T, −790 T/G and −735C/T) is associated with coronary triple-vessel disease. Matrix Biology. 2004;22:585-591. DOI: 10.1016/j.matbio.2003.10.004
133 - Rutter JL, Mitchell TI, Buttice G, Meyers J, Gusella JF, Ozelius LJ, et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an Ets binding site and augments transcription. Cancer Research. 1998;58:5321-5325
134 - Pearce E, Tregouet DA, Samnegard A, Morgan AR, Cox C, Hamsten A, et al. Haplotype effect of the matrix metalloproteinase-1 gene on risk of myocardial infarction. Circulation Research. 2005;97:1070-1076. DOI: 10.1161/01.res.0000189302.03303.11
135 - Hlatky MA, Ashley E, Quertermous T, Boothroyd DB, Ridker P, Southwick A, et al. Matrix metalloproteinase circulating levels, genetic polymorphisms, and susceptibility to acute myocardial infarction among patients with coronary artery disease. American Heart Journal. 2007;154:1043-1051. DOI: 10.1016/j.ahj.2007.06.042
136 - Cheng YC, Kao WH, Mitchell BD, O'Connell JR, Shen H, McArdle PF, et al. Genome-wide association scan identifies variants near matrix metalloproteinase (MMP) genes on chromosome 11q21-22 strongly associated with serum MMP-1 levels. Circulation. Cardiovascular Genetics. 2009;2:329-337. DOI: 10.1161/circgenetics.108.834986
137 - Wang H, Parry S, Macones G, Sammel MD, Ferrand PE, Kuivaniemi H, et al. Functionally significant SNP MMP8 promoter haplotypes and preterm premature rupture of membranes (PPROM). Human Molecular Genetics. 2004;13:2659-2669. DOI: 10.1093/hmg/ddh287
138 - Laxton RC, Hu Y, Duchene J, Zhang F, Zhang Z, Leung KY, et al. A role of matrix metalloproteinase-8 in atherosclerosis. Circulation Research. 2009;105:921-929. DOI: 10.1161/circresaha.109.200279
139 - Djuric T, Stankovic A, Koncar I, Radak D, Davidovic L, Alavantic D, et al. Association of MMP-8 promoter gene polymorphisms with carotid atherosclerosis: Preliminary study. Atherosclerosis. 2011;219:673-678. DOI: 10.1016/j.atherosclerosis.2011.08.025
140 - Li C, Jin XP, Zhu M, Chen QL, Wang F, Hu XF, et al. Positive association of MMP 14 gene polymorphism with vulnerable carotid plaque formation in a Han Chinese population. Scandinavian Journal of Clinical and Laboratory Investigation. 2014;74:248-253. DOI: 10.3109/00365513.2013.879731
141 - Lehrke M, Greif M, Broedl UC, Lebherz C, Laubender RP, Becker A, et al. MMP-1 serum levels predict coronary atherosclerosis in humans. Cardiovascular Diabetology. 2009;8:50. DOI: 10.1186/1475-2840-8-50
142 - Blankenberg S, Rupprecht HJ, Poirier O, Bickel C, Smieja M, Hafner G, et al. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation. 2003;107:1579-1585. DOI: 10.1161/01.cir.0000058700.41738.12
143 - Jefferis BJ, Whincup P, Welsh P, Wannamethee G, Rumley A, Lennon L, et al. Prospective study of matrix metalloproteinase-9 and risk of myocardial infarction and stroke in older men and women. Atherosclerosis. 2010;208:557-563. DOI: 10.1016/j.atherosclerosis.2009.08.018
144 - Tuomainen AM, Nyyssonen K, Laukkanen JA, Tervahartiala T, Tuomainen TP, Salonen JT, et al. Serum matrix metalloproteinase-8 concentrations are associated with cardiovascular outcome in men. Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2722-2728. DOI: 10.1161/atvbaha.107.154831
145 - Hasty KA, Jeffrey JJ, Hibbs MS, Welgus HG. The collagen substrate specificity of human neutrophil collagenase. The Journal of Biological Chemistry. 1987;262:10048-10052
146 - Momiyama Y, Ohmori R, Tanaka N, Kato R, Taniguchi H, Adachi T, et al. High plasma levels of matrix metalloproteinase-8 in patients with unstable angina. Atherosclerosis. 2010;209:206-210. DOI: 10.1016/j.atherosclerosis.2009.07.037
147 - Djuric T, Zivkovic M, Stankovic A, Kolakovic A, Jekic D, Selakovic V, et al. Plasma levels of matrix metalloproteinase-8 in patients with carotid atherosclerosis. Journal of Clinical Laboratory Analysis. 2010;24:246-251. DOI: 10.1002/jcla.20393
148 - Fertin M, Lemesle G, Turkieh A, Beseme O, Chwastyniak M, Amouyel P, et al. Serum MMP-8: A novel indicator of left ventricular remodeling and cardiac outcome in patients after acute myocardial infarction. PLoS One. 2013;8:e71280. DOI: 10.1371/journal.pone.0071280
149 - Brkic M, Balusu S, Libert C, Vandenbroucke RE. Friends or foes: Matrix metalloproteinases and their multifaceted roles in neurodegenerative diseases. Mediators of Inflammation. 2015;2015:620581. DOI: 10.1155/2015/620581
150 - Nelissen I, Vandenbroeck K, Fiten P, Hillert J, Olsson T, Marrosu MG, et al. Polymorphism analysis suggests that the gelatinase B gene is not a susceptibility factor for multiple sclerosis. Journal of Neuroimmunology. 2000;105:58-63
151 - Benesova Y, Vasku A, Stourac P, Hladikova M, Beranek M, Kadanka Z, et al. Matrix metalloproteinase-9 and matrix metalloproteinase-2 gene polymorphisms in multiple sclerosis. Journal of Neuroimmunology. 2008;205:105-109. DOI: 10.1016/j.jneuroim.2008.08.007
152 - He X, Zhang L, Yao X, Hu J, Yu L, Jia H, et al. Association studies of MMP-9 in Parkinson’s disease and amyotrophic lateral sclerosis. PLoS One. 2013;8:e73777. DOI: 10.1371/journal.pone.0073777
153 - La Russa A, Cittadella R, De Marco EV, Valentino P, Andreoli V, Trecroci F, et al. Single nucleotide polymorphism in the MMP-9 gene is associated with susceptibility to develop multiple sclerosis in an Italian case–control study. Journal of Neuroimmunology. 2010;225:175-179. DOI: 10.1016/j.jneuroim.2010.04.016
154 - Fernandes KS, Brum DG, Sandrim VC, Guerreiro CT, Barreira AA, Tanus-Santos JE. Matrix metalloproteinase-9 genotypes and haplotypes are associated with multiple sclerosis and with the degree of disability of the disease. Journal of Neuroimmunology. 2009;214:128-131. DOI: 10.1016/j.jneuroim.2009.07.004
155 - Djuric T, Zivkovic M, Stankovic A, Dincic E, Raicevic R, Alavantic D. Association of the MMP-3 5A/6A gene polymorphism with multiple sclerosis in patients from Serbia. Journal of the Neurological Sciences. 2008;267:62-65. DOI: 10.1016/j.jns.2007.09.037
156 - Gasparovic I, Cizmarevic NS, Lovrecic L, Perkovic O, Lavtar P, Sepcic J, et al. MMP-2 -1575G/A polymorphism modifies the onset of optic neuritis as a first presenting symptom in MS? Journal of Neuroimmunology. 2015;286:13-15. DOI: 10.1016/j.jneuroim.2015.06.014
157 - Reitz C, van Rooij FJ, Soares HD, de Maat MP, Hofman A, Witteman JC, et al. Matrix metalloproteinase 3 haplotypes and plasma amyloid beta levels: The Rotterdam study. Neurobiology of Aging. 2010;31:715-718. DOI: 10.1016/j.neurobiolaging.2008.05.033
158 - Reitz C, van Rooij FJ, de Maat MP, den Heijer T, Hofman A, Witteman JC, et al. Matrix metalloproteinase 3 haplotypes and dementia and Alzheimer’s disease. The Rotterdam Study. Neurobiol Aging. 2008;29:874-881. DOI: 10.1016/j.neurobiolaging.2007.01.001