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PubMed2006

Expression of tissue inhibitor of matrix metalloproteinase-1 in aging of transgenic mouse liver.

BACKGROUND: Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is related to the aging of many organs, but few data are available on the change of TIMP-1 in liver aging. The purpose of this study was to investigate the expression and role of TIMP-1, matrix metalloproteinase-2 (MMP-2) and MMP-9 in the process of natural aging in the livers of normal and transgenic mice, and to detect the effects of TIMP-1 on oxidative level and anti-oxidative ability of the livers of transgenic young mice. METHODS: Normal and transgenic mice were divided into 3 groups according to their age: 3-month-old group (n = 5), 12-month-old group (n = 5) and 24-month-old group (n = 5). Histopathological changes of the liver were observed after HE and Masson staining. The messenger RNA (mRNA) levels of TIMP-1, MMP-2 and MMP-9 were determined by semi-quantitative reverse transcriptional polymerase chain reaction; protein expression was measured by Western blot in the livers of normal and transgenic mice of various ages. Changes in levels of superoxide dismutase (SOD), monoamine oxidase (MAO), malondialdehyde (MDA) as well as oxidative and anti-oxidative ability were measured. RESULTS: Histologically, more fatty degeneration and collagen deposition were found in the aging livers of transgenic mice than in those of the normal mice as their age of months increased. The mRNA and protein expressions of TIMP-1 were significantly high in the oldest animals. The histopathological changes, mRNA and protein expressions of TIMP-1 increased significantly in the liver of transgenic mice as compared with normal mice. The expression of MMP-2 and MMP-9 showed a minor change in the process of aging. Liver change and collagen deposition were not observed in young mice, but the activity of SOD decreased (P < 0.05), and the activity of MAO (P < 0.01) and the content of MDA increased in the liver of transgenic mice (P < 0.01). CONCLUSIONS: The expression of TIMP-1 is significantly high in the liver of transgenic mouse in the process of aging, indicating that the oxidative level increases and the anti-oxidative ability decreases in the liver of transgenic mouse. TIMP-1 plays an important role in the process of liver aging.

Aging↗
PubMed2003

Matrix metalloproteinase-26 is expressed in human endometrium but not in endometrial carcinoma.

BACKGROUND: The human matrix metalloproteinase (MMP)-26, also called matrilysin-2 or endometase, has been isolated as a matrilysin (MMP-7) homolog. Matrix metalloproteinase-26 was expressed in tissue samples from the placenta and endometrial tumors and its expression may be related to the development of endometrial carcinomas. METHODS: Total RNAs were isolated from 5 endometrial carcinoma cell lines, 36 normal endometrial tissue samples, 4 hyperplasia tissue samples, and from 24 endometrial carcinoma tissue samples. Reverse transcription-polymerase chain reation (RT-PCR) was performed to detect MMP-26 mRNA expression. To identify MMP-26 mRNA localization and protein expression, we performed in situ RT-PCR and immunohistochemistry, respectively. RESULTS: Reverse transcription-polymerase chain reaction analysis revealed that MMP-26 mRNA was expressed in 24 of 36 normal human endometrial tissue samples. However, MMP-26 mRNA expression was not detected in endometrial carcinoma cell lines nor in endometrial carcinoma tissue samples except for one case. Western blot analysis showed similar results. In situ RT-PCR analysis revealed that MMP-26 expression was localized in the epithelial glandular cells but faint expression was observed in the stromal cells. Subsequently, we separated endometrial tissues into epithelial glandular and stromal cells. Using RT-PCR, the purified epithelial glandular cells exhibited MMP-26 mRNA expression but the purified stromal cells did not. Immunohistochemical analyses revealed that MMP-26 protein expression is also limited to endometrial epithelial glandular cells but not to cancer cells. Therefore, MMP-26 expression is limited to normal epithelial glandular cells. CONCLUSIONS: We found a significant difference in MMP-26 expression in normal and malignant endometrial tissue samples, although its function is still unknown. These data suggest that MMP-26 may be a candidate for a new tumor marker for endometrial carcinomas.

Blotting, Western↗
PubMed2000

Matrix metalloproteinases and tissue inhibitor of metalloproteinase-2 in fetal rabbit lung.

Cell-extracellular matrix interaction and extracellular matrix remodeling are known to be important in fetal lung development. We investigated the localization of matrix metalloproteinases (MMPs) in fetal rabbit lungs. Immunohistochemistry for type IV collagen, MMP-1, MMP-2, MMP-9, membrane type (MT) 1 MMP, and tissue inhibitor of metalloproteinase (TIMP)-2 and in situ hybridization for MMP-9 mRNA were performed. Gelatin zymography and Western blotting for MT1-MMP in lung tissue homogenates were also studied. MMP-1 and MT1-MMP were detected in epithelial cells, and MMP-2 and TIMP-2 were detected in epithelial cells and some mesenchymal cells in each stage. MMP-9 was found in epithelial cells mainly in the late stage. Gelatin zymography revealed that the ratio of active MMP-2 to latent MMP-2 increased dramatically during the course of development. MT1-MMP was detected in tissue homogenates, especially predominant in the late stage. These findings suggest that MMPs and their inhibitors may contribute to the formation of airways and alveoli in fetal lung development and that activated MMP-2 of alveolar epithelial cells may function to provide an extremely wide alveolar surface.

Animals↗
PubMed1999

Characterization of stromelysin 1 (MMP-3), matrilysin (MMP-7), and membrane type 1 matrix metalloproteinase (MT1-MMP) derived fibrin(ogen) fragments D-dimer and D-like monomer: NH2-terminal sequences of late-stage digest fragments.

Matrix metalloproteinases (MMPs) participate in physiological remodeling of the extracellular matrix. Recently we determined that both fibrinogen (Fg) and cross-linked fibrin (XL-Fb) are substrates for selected MMPs. Specifically, XL-Fb clots were solubilized by MMP-3 (stromelysin 1) by cleavage at gamma Gly 404-Ala 405, resulting in a D-like monomer fragment. Similarly, MMP-7 (matrilysin) and MT1-MMP (membrane type 1 matrix metalloproteinase) solubilized XL-Fb clots. However, the molecular mass of fragment D-dimer, obtained after MMP-7 and MT1-MMP degradation of XL-Fb, is similar to that of fragment D-dimer from plasmin degradation ( approximately 186 kDa). In contrast, fragment D-like monomer, from MMP-3 degradation of both fibrinogen (Fg) and XL-Fb, is similar to fragment D from plasmin degradation of Fg ( approximately 94 kDa). Reduced chains from MMP-3, MMP-7, and MT1-MMP digests of Fg and XL-Fb were subjected to direct sequence analyses and D/D-dimer alpha-chain showed cleavage at both alpha Asp 97-Phe 98 and alpha Asn 102-Asn 103. Degradation of the beta-chain resulted in microheterogeneity of cleavage sites at beta Asp 123-Leu 124, beta Asn 137-Val 138, and beta Glu 141-Tyr 142, whereas all three enzymes cleaved the gamma-chain at gamma Thr 83-Leu 84. In both Fg and XL-Fb, several cleavage sites obtained by proteolysis with MMP-3, MMP-7, and MT1-MMP were found to be in very close proximity to those obtained by plasmin on these same substrates. That does not occur with other MMPs such as MMP-1, -2, and -9 and MT2-MMP. The degradation of XL-Fb by MMPs suggests both plasmin-dependent and independent mechanisms of fibrinolysis that might be relevant in inflammation, angiogenesis, arthritis, and atherosclerosis.

Binding Sites↗
PubMed2003

Expression of matrix metalloproteinases (MMP-2 and -9) and their inhibitors (TIMP-1 and -2) in prostate cancer tissue.

Matrix metalloproteinases (MMPs) have been implicated in progression and metastases of different tumours. The balance between the MMPs and their natural inhibitors (tissue inhibitors of matrix metalloproteinases; TIMP) seems to be an important factor related to this role. Here, the expression of MMP-2 and -9 along with TIMP-1 and -2 was examined in prostate cancer tissue. A total of 40 radical prostatectomy specimens were embedded in paraffin and immunohistochemical staining was performed to detect MMP-2 and -9, and TIMP-1 and -2. The immunoreactivity was assessed semiquantitively using routine light microscopy. The intensity of staining was correlated to preoperative PSA, T category, Gleason score and clinical parameters of the specimens. The imbalance of MMPs and TIMPs was recognised as a significant loss of TIMP-1 in malignant epithelium and an upregulation of MMPs. Palpable tumours (T2, T3) expressed significantly more MMP-2 and significantly less MMP-9 than T1c tumours. Our data are in accordance with other literature reports in that an imbalance of MMPs and TIMPs is found in malignant tumours. The observed imbalance of MMP and TIMP is mainly caused by a loss of TIMP-1. Furthermore, palpable tumours demonstrated significantly more MMP-2 and significantly less MMP-9 expression than nonpalpable tumours.

Aged↗
PubMed1999

Leukolysin/MMP25/MT6-MMP: a novel matrix metalloproteinase specifically expressed in the leukocyte lineage.

A novel matrix metalloproteinase (MMP) was identified from leukocytes and found to be specifically expressed by peripheral blood leukocytes among 29 different tissues examined. Named leukolysin, it encodes for 562 residues with a conserved MMP structure, i.e., pre-, pro-, catalytic, hinge- and hemopexin-like domains, but also a RXK/RR motif, known for its role in MMP zymogen activation, and a C-terminal hydrophobic segment. Overall, leukolysin displays the strongest homology to the newly identified MT-MMP subgroup with 45% and 39% identities to MT4- and MT1-MMPs vs 30% and 31.5% to MMP1 and 3 respectively. Unlike MT4-MMP whose proteolytic activity remains undefined, a C-terminally truncated leukolysin is expressed as a strong gelatinolytic species at 28 kDa which is derived from a cell-associated 34 kDa proenzyme, presumably by furin or proprotein convertase mediated removal of the propeptide (approximately 6 kDa). By green fluorescent protein (GFP) tagging, the intracellular proenzyme is localized to granules throughout the cell, suggesting that activation occur immediately prior to secretion. Taken together, leukolysin may be part of the proteolytic arsenal deployed by leukocytes during inflammatory responses. Molecular cloning of a novel MMP: MMP:25

Amino Acid Sequence↗
PubMed2002

Identification and specific expression of matrix metalloproteinase-26 in rhesus monkey endometrium during early pregnancy.

Matrix metalloproteinases (MMPs) and their tissue inhibitors may play important roles in tissue remodelling processes of the uterus. This study identified MMP-26 (endometase/matrilysin-2) in the endometrium of pregnant rhesus monkeys (Macaca mulatta) and monitored the spatial and temporal expression of the transcript and protein in the uteri on days 12, 18 and 26 of pregnancy. The partial monkey MMP-26 gene sequence of 289 nucleotides was 98% identical to that of its human homologue and its protein fragment contained a PHCGVPDGSD sequence in the prodomain identical to that in human MMP-26. RT-PCR analysis demonstrated that the average level of MMP-26 mRNA in the endometrium was high on day 12 of pregnancy, but significantly decreased on days 18 and 26 (P < 0.05). In-situ hybridization confirmed that MMP-26 mRNA is specifically localized in the endometrial compartments, with intense signals in the glandular epithelium on day 12 and in the walls of spiral arterioles adjacent to the implantation site on day 26. The hybridization signal for MMP-26 mRNA in the glandular epithelium decreased dramatically on day 18 and was undetectable on day 26. No MMP-26 mRNA transcripts were detected in the placental villi on days 18 and 26. Immunohistochemistry showed that the expression pattern of MMP-26 protein was similar to that of its mRNA. The restricted expression pattern of MMP-26 in the monkey uterus implies that this new MMP is involved in the highly regulated tissue remodelling processes of the glandular epithelium and spiral arteries during early pregnancy.

Actins↗
PubMed2000

The Hematopoietic Microenvironment: Matrix Metalloproteinases in the Hematopoietic Microenvironment.

Matrix metalloproteinases (MMPs) are structurally and functionally related zinc-dependent endopeptidases capable of degrading the components of extracellular matrix (ECM) and basement membranes. MMPs participate in many physiological processes and have also been implicated in various pathological conditions including tumor invasion and metastasis. The functions of MMPs are known to be controlled by mechanisms leading to activation of their latent forms and through inhibition of both active and latent forms by natural tissue inhibitors of metalloproteinases (TIMPs). The complex relationships between MMPs and TIMPs within the bone marrow microenvironment during normal hematopoiesis as well as during leukemic growth and dissemination have not been extensively investigated. We reported that primary acute myelogenous leukemia (AML) blasts and leukemic KG-1 cells penetrate reconstituted basement membrane (Matrigel) in an in vitro invasion assay, secrete the gelatinases (MMP-2 and MMP-9) and express active MMP-2 on the cell surface. We also analyzed MMP/TIMP expression in normal bone marrow cells of the myeloid and stromal lineages and showed that MMP-2, MMP-9, TIMP-1 and TIMP-2 are produced in the bone marrow microenvironment. Furthermore, we examined the role of gelatinases in the transmigration of stem/progenitor cells from the bone marrow into peripheral blood. We found that steady-state bone marrow CD34(+) cells, unlike circulating peripheral blood CD34(+) cells, did not express MMP-2 and MMP-9 mRNA transcripts and proteins, and that various cytokines were able to upregulate expression of these MMPs in bone marrow CD34(+) cells and trans-Matrigel migration of these cells. Thus, we now have evidence that MMPs and TIMPs are constituents of the hematopoietic microenvironment although their roles in hematopoiesis have yet to be determined.

Journal Article↗
PubMed1998

Matrix metalloproteinases produced by rat IL-2-activated NK cells.

We have previously documented that adoptively transferred IL-2-activated NK (A-NK) cells can accumulate within cancer metastases. Electron microscopic studies of pulmonary metastases have revealed that adoptively transferred A-NK cells that accumulate within metastases bind to endothelial cells and are able to traverse basement membranes. We have now extended these morphologic studies. We report that rat A-NK cells produce two matrix metalloproteinases: MMP-2 and MMP-9, as determined by SDS-PAGE gelatin zymography. These activities are inhibited following incubation with BB-94 (batimastat), a specific inhibitor of matrix metalloproteinases but not with 3,4-dichloroisocoumarin, an inhibitor of neutral serine proteases. The identity of MMP-2 was confirmed by Western blots using a polyclonal Ab against human MMP-2, whereas reverse transcriptase-PCR analysis of mRNA extracts of A-NK cells has confirmed the presence of MMP-9. In addition, we report for the first time that A-NK cells can migrate through a model basement membrane-like extracellular matrix. Moreover, the ability of A-NK cells to migrate through this model basement membrane was partially inhibited by BB-94; however, BB-94 has no effect on A-NK cell-mediated cytotoxicity, suggesting that matrix metalloproteinases do not contribute to cytolytic function of A-NK cells. In sum, our studies show that A-NK cells employ BB-94-inhibitable matrix metalloproteinases to degrade extracellular matrices. This suggests that matrix metalloproteinases may play a role in the accumulation of A-NK cells within cancer metastases.

Animals↗
PubMed2006

Nicotine treatment induces expression of matrix metalloproteinases in human osteoblastic Saos-2 cells.

Tobacco smoking is an important risk factor for the development of severe periodontitis. Recently, we showed that nicotine affected mineralized nodule formation, and that nicotine and lipopolysaccharide stimulated the formation of osteoclast-like cells by increasing production of macrophage colony-stimulating factor (M-CSF) and prostaglandin E2 (PGE2) by human osteoblastic Saos-2 cells. In the present study, we examined the effects of nicotine on the expression of matrix metalloproteinases (MMPs), tissue inhibitors of matrix metalloproteinases (TIMPs), the plasminogen activation system including the component of tissue-type plasminogen activator (tPA), urokinase-type PA (uPA), and PA inhibitor type 1 (PAI-1), alpha7 nicotine receptor, and c-fos. We also examined the effect of the nicotine antagonist D-tubocurarine on nicotine-induced expression of MMP-1. Gene expression was examined using real-time polymerase chain reaction (PCR) to estimate mRNA levels. In addition, expression of the MMP, TIMP, uPA, tPA, and PAI-1 proteins was determined by Western blotting analysis. Nicotine treatment caused expression of MMP-1, 2, 3, and 13, but not MMP-14, to increase significantly after 5 or 10 d of culture; MMP-14 expression did not change through day 14. Enhancement of MMP-1 expression by nicotine treatment was eliminated by simultaneous treatment with D-tubocurarine. In the presence of nicotine, expression of uPA, PAI-1, or TIMP-1, 2, 3, or 4 did not change over 14 d of culture, whereas expression of tPA increased significantly by day 7. Nicotine also increased expression of the alpha7 nicotine receptor and c-fos genes. These results suggest that nicotine stimulates bone matrix turnover by increasing production of tPA and MMP-1, 2, 3, and 13, thereby tipping the balance between bone matrix formation and resorption toward the latter process.

Cell Line, Tumor↗
PubMed1999

Shedding of membrane type 1 matrix metalloproteinase in a human breast carcinoma cell line.

Membrane type 1 matrix metalloproteinase (MT1-MMP) with a transmembrane domain is a new member of the MMP gene family and is expressed on the cell surfaces of many carcinoma cells to activate the zymogen of MMP-2 (gelatinase A). We have previously reported that MT1-MMP is released into culture media in a complex form with tissue inhibitor of metalloproteinases 2 (TIMP-2) from a human breast carcinoma cell line, MDA-MB-231, treated with concanavalin A (Con A). In the present study, we further studied the release mechanism of MT1-MMP. Immunoblot analysis indicated that the amounts of MT1-MMP in culture media increase with the time of exposure and the concentration of Con A, and those in cell lysates conversely decrease in a similar way. Time- and dose-dependent release of MT1-MMP into the media was confirmed by a sandwich enzyme immunoassay specific to MT1-MMP. The molecular weight of the immunoreactive MTI-MMP in the media was Mr 56,000, which was 4,000-Mr smaller than that in the cell lysates. Northern blot analysis demonstrated that the mRNA expression level of MT1-MMP is about 3-fold enhanced after a 24 h-exposure to Con A and this is maintained up to 72-h exposure. The release of MT1-MMP from the Con A-treated cells was inhibited by metalloproteinase inhibitors such as EDTA and o-phenanthroline, but not by MMP inhibitors including TIMP-1, TIMP-2 and BB94 or other proteinase inhibitors of serine, cysteine and aspartic proteinases. During the Con A treatment of the cells, cell viability decreased time- and dose-dependently and dead cells reacted positively in the TdT-mediated dUTP Nick-End Labeling (TUNEL) method. Con A-treated MDA cells showed apoptotic morphology when stained with Hoechst dye and hematoxylin and eosin. DNA ladder formation was detected by electrophoresis of the DNA from Con A-treated MDA cells. These results suggest that MT1-MMP release from Con A-treated cells is due to shedding mediated by metalloproteinase(s) other than MMPs, and is associated with apoptosis.

Apoptosis↗
PubMed2002

Matrix metalloproteinases and neuroinflammation in multiple sclerosis.

Matrix metalloproteinases (MMPs) are extracellular matrix remodeling neutral proteases that are important in normal development, angiogenesis, wound repair, and a wide range of pathological processes. Growing evidence supports a key role of the MMPs in many neuroinflammatory conditions, including meningitis, encephalitis, brain tumors, cerebral ischemia, Guillain-Barré, and multiple sclerosis (MS). The MMPs attack the basal lamina macromolecules that line the blood vessels, opening the blood-brain barrier (BBB). They contribute to the remodeling of the blood vessels that causes hyalinosis and gliosis, and they attack myelin. During the acute inflammatory phase of MS, they are involved in the injury to the blood vessels and may be important in the disruption of the myelin sheath and axons. Normally under tight regulation, excessive proteolytic activity is detected in the blood and cerebrospinal fluid in patients with acute MS. Because they are induced in immunologic and nonimmunologic forms of demyelination, they act as a final common pathway to exert a "bystander" effect. Agents that block the action of the MMPs have been shown to reduce the damage to the BBB and lead to symptomatic improvement in several animal models of neuroinflammatory diseases, including experimental allergic encephalomyelitis. Such agents may eventually be useful in the control of excessive proteolysis that contributes to the pathology of MS and other neuroinflammatory conditions.

Animals↗
PubMed2000

Polymorphism in matrix metalloproteinase gene promoters: implication in regulation of gene expression and susceptibility of various diseases.

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

Disease Susceptibility↗
PubMed1999

Expression of matrix metalloproteinase-1, -2 and -3 in squamous cell carcinoma and actinic keratosis.

Matrix metalloproteinase (MMP) plays an important role in extracellular matrix degradation associated with cancer invasion. An expression of MMP-1 (interstitial collagenase), MMP-2 (72-kDa type IV collagenase) and MMP-3 (stromelysin-1) was investigated in squamous cell carcinoma (SCC) and its precancerous condition, actinic keratosis (AK), using in situ hybridization techniques. MMP-1 mRNA was detected in tumour cells and/or in stromal cells in all cases of SCC, four of six AKs adjacent to SCC and four of 16 AKs. MMP-2 and MMP-3 mRNAs were detected in SCC but not in AK. The expression of MMP-3 correlated to that of MMP-1 (P = 0.03) localized at the tumour mass and stroma of the invasive area, while MMP-2 mRNA was detected widely throughout the stroma independent of MMP-1 expression. Our results indicated that the expression of MMP-1, -2 and -3 showed different localization patterns, suggesting a unique role of each MMP in tumour progression. Moreover, MMP-1 expression could be an early event in the development of SCC, and AK demonstrating MMP-1 mRNA, might be in a more advanced dysplastic state, progressing to SCC.

Carcinoma, Squamous Cell↗
PubMed1997

Genes of the membrane-type matrix metalloproteinase (MT-MMP) gene family, MMP14, MMP15, and MMP16, localize to human chromosomes 14, 16, and 8, respectively.

The membrane-type matrix metalloproteinases (MT-MMPs) constitute a newly discovered family of four enzymes within the matrix metalloproteinase (MMP) superfamily. We have mapped the genes for MT1-MMP (MMP14), MT2-MMP (MMP15), and MT3-MMP (MMP16) using in situ hybridization to human metaphase chromosomes. In contrast to the genes for many MMPs that are clustered on chromosome 11, the genes MMP14, MMP15, and MMP16 all map to distinct chromosomes. MMP14 maps to human chromosome 14, MMP15 to human chromosome 16, and MMP16 to human chromosome 8.

Cells, Cultured↗
PubMed2002

Upregulation of extracellular matrix metalloproteinase inducer (EMMPRIN) and gelatinases in human atherosclerosis infected with Chlamydia pneumoniae: the potential role of Chlamydia pneumoniae infection in the progression of atherosclerosis.

Chlamydia pneumoniae infection implicated as an important etiologic factor of atherosclerosis, especially in coronary artery disease (CAD), was found in vitro to be associated with the induction of matrix metalloproteinases (MMPs). An extracellular matrix metalloproteinase inducer (EMMPRIN)/ membrane-type 1 matrix metalloproteinase (MT1-MMP) system which induces and activates MMPs, is suggested to be functional and were upregulated in the failing myocardium. However, the upstream regulation of MMPs by C. pneumoniae within atheroma itself remains unclear. We evaluated the seroepidemiologic study of C. pneumoniae infection in CAD patients (n= 391) and controls (n=97) and performed histopathological and in vitro analysis in atherosclerotic vascular tissues obtained from patients with seropositive to C. pneumoniae (n=20), by using immunochemistry for C. pneumoniae, EMMPRIN/MT1-MMP, MMP-2, and MMP-9. The seropositive rates of both anti-C. pneumoniae IgG and IgA were 56.7% in CAD group and 43.3% in control group (P=0.033). Seropositive rate was increased in subgroups of CAD patients without conventional coronary risk factors compared to those with conventional risk factors. Immunoreactivities of EMMPRIN, MT1-MMP, MMP-2, and MMP-9 were increased in the atheromatous plaque itself, predominantly in immunoreactive macrophages/mononuclear cells to C. pneumoniae. Furthermore, Western blot analysis showed that EMMPRIN and MMP-2 were detected more prominently in atherosclerotic tissues infected with C. pneumoniae compared to control tissues. Zymographic analysis revealed that activities of MMP-2 and MMP-9 were more increased in atherosclerotic tissues infected with C. pneumoniae compared to control tissues. The present study demonstrated upstream regulation of MMPs can be induced by C. pneumoniae within atheromatous plaque itself. These findings help to understand the potential role of C. pneumoniae in the progression of atherosclerosis.

Aged↗
PubMed2002

Prospective, randomized, double-blind trial investigating the effect of doxycycline on matrix metalloproteinase expression within atherosclerotic carotid plaques.

BACKGROUND AND PURPOSE: Elevated levels of matrix metalloproteinases (MMPs), particularly MMP-1 and MMP-9, have been implicated in plaque rupture. It has been suggested that inhibition of MMPs may stabilize vulnerable atherosclerotic plaques and improve clinical outcome. The aim of the study was to investigate the ability of doxycycline, a nonspecific MMP inhibitor, to reduce MMP concentration in carotid atheroma. METHODS: The study design was a prospective, double-blind randomized trial. One hundred patients requiring carotid endarterectomy were randomized to receive 200 mg/d doxycycline or placebo for 2 to 8 weeks before surgery. During endarterectomy, carotid plaques were retrieved. The concentrations of MMPs and doxycycline were determined in the atherosclerotic tissue by enzyme-linked immunosorbent assay and high-performance liquid chromatography, respectively. Clinical events were recorded, as was the rate of preoperative embolization (transcranial Doppler). RESULTS: Analysis of endarterectomized specimens demonstrated a mean doxycycline concentration of 6.0 micro g/g wet weight in treated patients. Administration of doxycycline significantly reduced the concentration of MMP-1 in carotid plaques from a mean of 14.8 to 10.3 ng/100g wet weight (P=0.038). This difference was due to decreased MMP-1 transcript (P<0.001). There was no difference in any other MMP (MMP-2, -3, or -9) or tissue inhibitor of matrix metalloproteinases-1 or -2. CONCLUSIONS: Doxycycline penetrated atherosclerotic plaques with acceptable tissue levels. This resulted in a reduction in MMP-1 concentration because of decreased expression.

Aged↗
PubMed2007

The matrix metalloproteinases (MMPS) in the decidua and fetal membranes.

The role of the matrix metalloproteinases (MMPs) in the decidua, fetal membranes and amniotic fluid (AF) has been receiving more and more attention. The MMPs are not only important intermediaries in pathological processes leading to preterm labor but it seems that they also play a crucial role in the activation of labor at term. During normal gestation MMP-1, -2, -3, -7 and -9 are found in the amniotic fluid and fetal membranes. MMP-2 and MMP-3 are expressed constitutively while MMP-9 is barely detectable until labor. At labor, while MMP-9 is the major MMP responsible for gelatinolytic activity in the membranes, MMP-2 is dominant in the decidua. MMP-7 (AF) increases with gestation but does not appear to play a major role in labor. The expression of MMPs is attenuated through the expression of relaxins, integrins and extracellular matrix metalloproteinase inducer (EMMPRIN). Spontaneous preterm delivery (PTD) may be a product of preterm labor (PTL), preterm premature rupture of membranes (P-PROM) or placental abruption. Each of these processes may have differing pathways but the presence of an intrinsic inflammatory response with or without infection seems to involve all etiologies. The inflammatory response is mediated with cytokines such as interleukins -1, -6 and -8 and tumor necrosis factor alpha. MMP-3, MMP-7 and MMP-8 appear to be important in these processes. MMP-9, which is the major MMP involved in normal labor, plays an important role in pathological labor as well. Finally, apoptosis seems to play a role in pathological labor, particularly deliveries involving P-PROM. African-American are at greater risk of PTD than white or Hispanic Americans. Environmental differences may not suffice to explain this phenomenon. Genetic polymorphisms of the MMP genes may help explain the greater risk among this population. Finally, manipulating MMPs may have a role in the prevention of PTD. Agents suggested include indomethacin, N-acetylcysteine, progesterone and specific inhibitors of phosphodiesterase 4.

Decidua↗