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PubMed2005

High serum levels of matrix metalloproteinase-9 and matrix metalloproteinase-1 are associated with rapid progression in patients with metastatic melanoma.

PURPOSE: Matrix metalloproteinases (MMP) are proteolytic enzymes that play an important role in various aspects of cancer progression. In the present work, we have studied the prognostic significance of serum levels of gelatinase B (MMP-9), collagenase-1 (MMP-1), and collagenase-3 (MMP-13) in patients with advanced melanoma. EXPERIMENTAL DESIGN: Total pretreatment serum levels of MMP-9 in 71 patients and MMP-1 and MMP-13 in 48 patients were determined by an assay system based on ELISA. Total MMP levels were also assessed in eight healthy controls. The active and latent forms of MMPs were defined by using Western blot analysis and gelatin zymography. RESULTS: Patients with high serum levels of MMP-9 (> or = 376.6 ng/mL; n = 19) had significantly poorer overall survival (OS) than patients with lower serum MMP-9 levels (n = 52; median OS, 29.1 versus 45.2 months; P = 0.033). High MMP-9 levels were also associated with visceral or bone metastasis (P = 0.027), elevated serum alkaline phosphatase level (P = 0.0009), and presence of liver metastases (P = 0.032). Serum levels of MMP-1 and MMP-13 did not correlate with OS. MMP-1 and MMP-9 were found mainly in latent forms in serum, whereas the majority of MMP-13 in serum was active (48 kDa) form. MMP-13 was found more often in active form in patients (mean, 99% of the total MMP-13 level) than in controls (mean, 84% of the total MMP-13 level; P < 0.0001). After initiating the therapy, patients with elevated levels of MMP-1 (> or = 29.8 ng/mL, n = 10) progressed more rapidly than patients with lower levels (median, 1.9 versus 3.5 months; P = 0.023). Serum levels of MMP-9 and MMP-13 did not correlate with the time to progression (TTP). In multivariate analysis with age and gender, MMP-9 or MMP-1 turned out to be independent prognostic factors for OS [P = 0.039; hazard ratio (HR), 1.8; 95% confidence interval (95% CI), 1.03-3.3] or TTP (P = 0.023; HR, 2.7; 95% CI, 1.15-6.4), respectively. CONCLUSIONS: Our findings provide evidence that MMP-1, MMP-9, and MMP-13 play important roles at different phases of metastatic melanoma spread and that serum MMP-9, in particular, could have clinical value in identifying patients at high risk for melanoma progression.

Adult↗
PubMed2002

A unique substrate binding mode discriminates membrane type-1 matrix metalloproteinase from other matrix metalloproteinases.

In our study, we characterized the substrate recognition properties of membrane type-1 matrix metalloproteinase (MT1-MMP; also known as MMP-14), a key enzyme in tumor cell invasion and metastasis. A panel of optimal peptide substrates for MT1-MMP was identified using substrate phage display. The substrates can be segregated into four groups based on their degree of selectivity for MT1-MMP. Substrates with poor selectivity for MT1-MMP are comprised predominately of the Pro-X-X- downward arrow-X(Hy) motif that is recognized by a number of MMPs. Highly selective substrates lack the characteristic Pro at the P(3) position; instead they contain an Arg at the P(4) position. This P(4) Arg is essential for efficient hydrolysis and for selectivity for MT1-MMP. Molecular modeling indicates that the selective substrates adopt a linear conformation that extends along the entire catalytic pocket of MT1-MMP, whereas non-selective substrates are kinked at the conserved P(3) Pro residue. Importantly, the selective substrates can be made non-selective by insertion of a proline kink at P(3), without significantly reducing overall k(cat)/K(m) values. Altogether the study provides a structural basis for selective and non-selective substrate recognition by MT1-MMP. The findings in this report are likely to explain several aspects of MT1-MMP biology.

Catalytic Domain↗
PubMed2005

Difference in expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 in patients with persistent ovarian cysts.

Matrix metalloproteinase-1 (MMP-1), MMP-2, and MMP-9 expression with real-time quantitative polymerase chain reaction were analyzed in endometriotic and nonendometriotic ovarian cysts. Although MMP-1 was not detected, MMP-9 and MMP-2 were expressed in all of the cysts. In particular, in five of six nonendometriotic cysts (83.3%) MMP-2 expression was higher than in endometriotic cysts. These data may represent new molecular elements helpful in differential diagnosis of endometriotic lesions.

Chronic Disease↗
PubMed2004

In vitro induction of matrix metalloproteinase-2 and matrix metalloproteinase-9 expression in keratinocytes by boron and manganese.

Matrix metalloproteinase (MMP)-2 and MMP-9 are involved in keratinocyte migration and granulation tissue remodeling during wound healing. Thermal water cures are sometimes proposed as complementary treatment for accelerating healing of wounds resulting from burns and/or surgery, but their mechanisms of action remain unknown. Some thermal waters are rich in trace elements such as boron and manganese. Interestingly, clinical studies have shown the beneficial effects of trace elements such as boron and manganese for human wound healing. To try to specify the role of trace elements in cutaneous healing, the present study investigated the effects of these trace elements on the production of MMP-2 and MMP-9 by normal human keratinocytes cultured in vitro. Immunohistochemistry and Western blot showed that intracellular MMP-9 expression in keratinocytes was induced when incubated for 6 h with boron at 10 micro g/ml or manganese at 0.2 micro g/ml. Moreover, gelatin zymography on keratinocyte supernatants showed an increase of gelatinase secretion after 24 h of incubation of keratinocytes with boron or manganese, regardless of concentration. Gelatinase secretion was not associated with keratinocyte proliferation induced by trace elements. Thus, our results suggest that boron and manganese could play a role in the clinical efficiency of thermal water on wound healing.

Blotting, Western↗
PubMed2005

Matrix metalloproteinase-2 and matrix metalloproteinase-9 type IV collagenases in serum of patients with pleural effusions.

Matrix metalloproteinases (MMPs) are proteolytic enzymes that are essentially involved in the turnover of the extracellular matrix (ECM). Recently, several MMPs were implicated in creating an environment that supports the initiation and maintenance of tumor growth. We verified MMP activity in the sera of patients with pleural effusions by gelatin zymography. Of these patients, 22 had malignant pleural effusion, consisting of 11 breast carcinomas and 11 lung carcinomas (7 squamous cell carcinomas and 4 adenocarcinomas), and 8 patients had benign effusions. The sera of 25 healthy subjects were used as controls. Zymography analysis showed three major gelatinolytic bands of 72, 92 and 220 kDa. The MMP-9/MMP-2 ratio was enhanced in cancer patients compared with benign diseases and healthy individuals. Furthermore, we determined the circulating levels of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (Ca 19-9), carbohydrate antigen 15-3 (Ca 15-3). The serum levels of Ca 15-3 were above the cut-off levels in several cancer patients. No correlation between gelatinolytic activity and high tumoral marker values was found.

Adolescent↗
PubMed2004

Increased intrahepatic cyclooxygenase 2, matrix metalloproteinase 2, and matrix metalloproteinase 9 expression is associated with progressive liver disease in chronic hepatitis C virus infection: role of viral core and NS5A proteins.

BACKGROUND: Cyclooxygenase 2 (COX-2) and matrix metalloproteinases (MMPs) have been implicated in tissue injury and fibrogenesis in animal models but little is known regarding their role in hepatitis C virus (HCV) related liver disease in humans. AIMS: To characterise the intrahepatic expression pattern of COX-2 and MMPs in chronic HCV infection and determine whether HCV core and NS5A proteins could promote their expression in cultured hepatocyte derived cell lines. PATIENTS: Thirty two anti-HCV+ and 10 anti-HCV- patients were studied. METHODS: Western blot, reverse transcription-polymerase chain reaction (RT-PCR), enzyme immunoassay, and immunohistochemistry were used to assess the expression pattern of COX-2 and MMPs in liver biopsy samples from all patients. COX-2 gene expression and MMP-9 protein levels were also determined by immunoblot, RT-PCR, and luciferase assays in core and NS5A transfected hepatocyte derived cells. RESULTS: The intrahepatic expression level of COX-2, MMP-2, and MMP-9 was significantly higher in HCV+ than in HCV- patients, increasing with the fibrotic stage of liver disease. We further demonstrated that COX-2 mRNA, protein, and activity were induced in resting and activated core and NS5A transfectants. Both viral proteins induced transcriptional activity of the COX-2 gene promoter whereas core, but not NS5A, exerted an inducer effect on MMP-9 protein levels in cultured hepatocyte derived cells. CONCLUSIONS: Intrahepatic COX-2, MMP-2, and MMP-9 overexpression is associated with progressive hepatic fibrosis in chronic HCV infection, suggesting their pathogenic role in fibrogenesis. HCV core and NS5A proteins were able to upregulate COX-2 and MMP-9 gene expression in hepatocyte derived cells, providing a potential mechanism for hepatic fibrosis during chronic HCV infection.

Adult↗
PubMed1997

Positive correlation between inhibitors of matrix metalloproteinase 1 and matrix metalloproteinases in malignant ovarian tumor tissues.

To investigate the relation between matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) in malignant ovarian tumor, MMP and TIMP activities in conditioned media of 16 malignant ovarian tumor tissues and six normal ovaries were detected by zymography and reverse zymography, respectively and were quantitated with a densitometer. TIMP-1 and TIMP-2 were detected in all normal and malignant ovarian tumor tissues by reverse zymography. In normal ovaries, the intensity of TIMP-2 bands was stronger than TIMP-1, but in malignant tumor tissues those of TIMP-1 were stronger. The ratios of TIMP-1 to TIMP-2 and MMP-9 to MMP-2 were significantly higher in malignant tumor tissues than in normal ovaries (P < 0.001). TIMP activity consisting of TIMP-1 and TIMP-2 correlated significantly to MMP activity of MMP-2 and MMP-9 (r = 0.67, P < 0.005). There was a significant correlation between TIMP-1 activity and MMP activity (r = 0.72, P < 0.001), but no correlation was observed between TIMP-2 activity and MMP activity. The high level of TIMP-1 appeared to be related to malignant phenotype in ovaries as well as the high level of MMP-9.

Adolescent↗
PubMed2002

Matrix metalloproteinase-1 and matrix metalloproteinase-3 gene promoter polymorphisms are associated with carotid artery stenosis.

BACKGROUND AND PURPOSE: The matrix metalloproteinases (MMPs) are a family of enzymes that are important in the resorption of extracellular matrix and are involved in atherogenesis. Recently, 2 common polymorphisms on MMP-1 (1G/2G) and MMP-3 (5A/6A) gene promoters have been described. The aim of this study was to investigate a possible association between MMP polymorphisms and increased risk of internal carotid artery (ICA) stenosis. METHODS: We studied 91 patients consecutively recruited for ICA stenosis who had undergone carotid endarterectomy and 133 subjects without ICA stenosis (controls). Polymorphic genotypes were determined by polymerase chain reaction and sequencing analysis. RESULTS: The frequency of the 6A allele was significantly different between cases and controls: 0.62 and 0.50, respectively (odds ratio [OR], 1.58; 95% CI, 1.08 to 2.33; P=0.017). The frequency of 6A/6A genotype was significantly higher in cases with involvement of both carotids (OR, 3.13; 95% CI, 1.14 to 8.5; P=0.026) and in patients with stenosis >70% (OR, 2.55; 95% CI, 1.07 to 6.07; P=0.033). No significant differences were observed in MMP-1 distribution. Patients who were homozygous for both the 6A and 2G alleles had an elevated relative risk of ICA stenosis (OR, 2.66; 95% CI, 1.23 to 5.72; P=0.016). Multiple logistic regression analysis using the common risk factors and the 6A and 2G allele variants revealed that the 6A allele was an independent risk factor for ICA stenosis (P=0.049). When 6A/6A and 2G/2G were combined, the risk factor for ICA stenosis was 3-fold higher (OR, 3.31; 95% CI, 1.48 to 7.42; P=0.004). CONCLUSIONS: Homozygosity for the 6A allele of the MMP-3 promoter is associated with carotid stenosis and, in association with MMP-1 2G homozygosity, predicts an increased risk of ICA stenosis. Even if obtained from a relatively limited patient series, these results might have relevant implications for treatment of ICA stenosis and possibly prevention of carotid-related stroke.

Alleles↗
PubMedDate not supplied

Relationship between expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 and invasion ability of cervical cancer cells.

Constitutive overexpression of matrix metalloproteinases (MMPs) is frequently observed in malignant tumors. MMPs are a family of zinc endopeptidases consisting of at least 20 different members. In particular, MMP-2 and MMP-9 are reported to be closely associated with invasion and metastasis in several cancers. We investigated whether expression of MMP-2 and MMP-9 is associated with invasion ability of seven cervical cancer cells by administration of o-phenanthroline as MMP inhibitor. In two cell lines, Siha and Caski, MMP-2 mRNA and protein were expressed at high levels. After treatment with o-phenanthroline, the rate of invasion in these two cell lines was significantly decreased. In contrast, in the other two cell lines, HT-3 and Caski, high levels of MMP-9 mRNA and protein were expressed but there was no decrease in the rate of invasion in these cells after treatment with o-phenanthroline. The data suggest that expression level of MMP-2 mRNA may regulate with invasion ability of cervical cancer.

Female↗
PubMed2001

Overexpression of matrix metalloproteinase-10 and matrix metalloproteinase-3 in human diabetic corneas: a possible mechanism of basement membrane and integrin alterations.

We have previously described decreased immunostaining of nidogen-1/entactin; laminin chains alpha1, alpha5, beta1,gamma1; and epithelial integrin alpha3beta1 in human diabetic retinopathy (DR) corneas. Here, using 142 human corneas, we tested whether these alterations might be caused by decreased gene expression levels or increased degradation. By semiquantitative reverse transcription-polymerase chain reaction, gene expression levels of the alpha1, alpha5, and beta1 laminin chains; nidogen-1/entactin; integrin alpha3 and beta1 chains in diabetic and DR corneal epithelium were similar to normal. Thus, the observed basement membrane and integrin changes were unlikely to occur because of a decreased synthesis. mRNA levels of matrix metalloproteinase-10 (MMP-10/stromelysin-2) were significantly elevated in DR corneal epithelium and stroma, and of MMP-3/stromelysin-1, in DR corneal stroma. No such elevation was seen in keratoconus corneas. These data were confirmed by immunostaining, zymography, and Western blotting. mRNA levels of five other proteinases and of three tissue inhibitors of MMPs were similar to normal in diabetic and DR corneal epithelium and stroma. The data suggest that alterations of laminins, nidogen-1/entactin, and epithelial integrin in DR corneas may occur because of an increased proteolytic degradation. MMP-10 overexpressed in the diabetic corneal epithelium seems to be the major contributor to the observed changes in DR corneas. Such alterations may bring about epithelial adhesive abnormalities clinically seen in diabetic corneas.

Adult↗
PubMed2003

Donor spontaneous intracerebral hemorrhage is associated with systemic activation of matrix metalloproteinase-2 and matrix metalloproteinase-9 and subsequent development of coronary vasculopathy in the heart transplant recipient.

BACKGROUND: Matrix metalloproteinase (MMP)-2 and MMP-9 have been shown to play a role in the progression of hemorrhagic stroke. We hypothesized that donor intracerebral hemorrhage (ICH) is associated with activation of the metalloproteinases before transplantation that play a key role in the subsequent development of transplant vasculopathy. METHODS AND RESULTS: We evaluated mRNA expressions of MMP-2 and MMP-9 in donor spleen lymphocytes (before transplantation) and in heart biopsies at 1 week after transplantation in 20 recipients from ICH donors and 20 recipients from trauma donors. Patients underwent serial coronary intravascular ultrasound, and interstitial myocardial fibrosis was quantified at 1 year. The baseline characteristics were similar except for increased donor age in the ICH group. Heart biopsies from the ICH group showed significant increased expression of MMP-2 (17-fold, P<0.0001) and MMP-9 (20-fold, P<0.0001) compared with the trauma group. Furthermore, the ICH group showed 1.8-fold (P=0.016) increased mRNA expression of MMP-2 and 1.7-fold (P=0.015) increased mRNA expression of MMP-9 in the donor spleen lymphocytes, suggesting the presence of systemic activation of metalloproteinases before transplantation. At 1 year, the ICH group showed increased myocardial fibrosis and accelerated coronary vasculopathy. Using multivariate regression analysis, MMP-9 was found to be associated with increased risk for vasculopathy independent of donor age (OR, 2.41; P=0.01; 95% CI, 1.24 to 4.69). CONCLUSIONS: This is the first report to describe systemic activation of MMP-2 and MMP-9 in donors with intracerebral hemorrhage and subsequent development of allograft vasculopathy.

Adult↗
PubMed1999

Progesterone analogues similarly modulate endometrial matrix metalloproteinase-1 and matrix metalloproteinase-3 and their inhibitor in a model for long-term contraceptive effects.

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in normal menstruation, while MMP-1 and MMP-3 production by human endometrial stromal cells (HESCs) is repressed in vitro by progesterone. We postulated that the repression by synthetic progestins of MMP production from HESCs may not be fully maintained in the long term, and that this may account for the disturbed uterine bleeding patterns in women using long-acting progestins. In this study, a long-term HESC culture model was established to compare the effects of natural progesterone and a number of synthetic analogues (ORG2058, medroxyprogesterone acetate, norethindrone acetate, levonorgestrel and drospirenone) on the production by these cells of MMP-1 and MMP-3 and TIMP-1. Zymographic and enzyme-linked immunosorbent analysis of culture medium after 2 weeks showed that both natural progesterone and all of the synthetic progestins tested maintained a significant inhibition of MMP-1 and MMP-3 production. Production of mRNA for MMP-1 and MMP-3 was also suppressed by all progestins, while TIMP production was increased. Thus, menstrual bleeding disturbances which occur during the use of synthetic progestins is not likely to result directly from changes in the effect of long-term progestin exposure on MMP-1 or MMP-3 or TIMP-1 production by HESCs.

Adult↗
PubMed1997

Reduction of serum matrix metalloproteinase 1 and matrix metalloproteinase 3 in rheumatoid arthritis patients following anti-tumour necrosis factor-alpha (cA2) therapy.

Matrix metalloproteinase (MMP)-1 and MMP-3 levels were measured in serum samples from rheumatoid arthritis (RA) patients undergoing a double-blinded placebo-controlled trial with the chimaeric anti-tumour necrosis factor (TNF)-alpha antibody cA2. Both MMP-1 (P < 0.015), but to a larger extent MMP-3 (P < 0.001) levels were elevated in all RA patients prior to the commencement of the trial compared with normal control sera. Following cA2 therapy, MMP-1 and MMP-3 levels were assessed in the placebo, and 1 and 10 mg/kg cA2-treated groups at 7, 14, 21 and 28 days. In both the 1 and the 10 mg/kg cA2-treated groups, a significant decrease in serum MMP-3 levels at all time points was observed, reducing maximally to 41% of pre-infusion values at day 7. MMP-1 levels were also reduced, but less dramatically than MMP-3, to 85% of pre-infusion values after 14 days in the 10 mg/kg cA2 treated group. In a separate non-placebo-controlled study, we also evaluated the tissue inhibitor of metalloproteinase (TIMP)-1 levels in plasma following cA2 infusion. Pre-infusion TIMP-1 levels were above the normal control range, but were significantly reduced (P < 0.035) 14 days after infusion to 72% of pre-infusion values. This study confirms previous reports that MMP-3 levels are elevated and correlate with measures of inflammation in RA, and furthermore demonstrate that serum MMP-3 and MMP-1 levels are downmodulated following anti-TNF-alpha antibody therapy. Whilst serum MMP-3 levels correlated with C-reactive protein (CRP) both prior to and following anti-TNF-alpha antibody therapy, it remains to be demonstrated that serum MMP-3 and/or MMP-1 levels reflect the cartilage and bone resorptive processes which are evident in this disease.

Antibodies, Monoclonal↗
PubMed2001

Evaluation of collagenase activity, matrix metalloproteinase-8, and matrix metalloproteinase-13 in horses with chronic obstructive pulmonary disease.

OBJECTIVES: To determine collagenase activity and evaluate matrix metalloproteinase (MMP)-8 and MMP-13 in horses with chronic obstructive pulmonary disease (COPD). ANIMALS: 12 horses with COPD and 12 healthy control horses. PROCEDURE: Collagenase activity was determined by use of an assay for degradation of type-I collagen. Western immunoblot analysis was used to identify interstitial collagenases MMP-8 and MMP-13 in tracheal epithelial lining fluid (TELF). Immunocytochemistry and in situ hybridization were used to determine cellular expression of these 2 collagenases in cells in bronchoalveolar lavage fluid (BALF). RESULTS: Collagenase activity was approximately 7 times higher in samples obtained from horses with COPD, compared with control horses. During stabling, horses with COPD had significantly higher collagenase activity than after being maintained on summer pasture, when activity was similar to that of control horses. Immunoreactivity of MMP-8 and MMP-13 was significantly increased in TELF of horses with COPD, compared with healthy horses. In TELF, a positive correlation was detected between immunoreactivity of MMP-8 and MMP-13 and the amount of degradation of type-I collagen. Macrophages and epithelial cells were the major cellular sources of MMP-8 and MMP-13. CONCLUSIONS AND CLINICAL RELEVANCE: Increased collagenase activity in TELF indicates active ongoing disease and, thus, may reflect lung tissue changes in horses with COPD. Measurements of collagenase activity and MMP immunoreactivity may provide additional diagnostic tools to identify the active phase of chronic lung disease.

Animals↗
PubMed2005

Different roles for matrix metalloproteinase-2 and matrix metalloproteinase-9 in the pathogenesis of cardiac allograft rejection.

Recent studies have shown an increased expression of several matrix metalloproteinases (MMP) during cardiac, renal and pulmonary allograft rejection. To further define the roles of MMP-2 and MMP-9 in the pathogenesis of cardiac allograft rejection, BALB/c cardiac allografts were transplanted into MMP-2-deficient (-/-) and MMP-9-/- mice. Allografts rejected by wild-type mice revealed a significant increase in MMP-2 and MMP-9 expression. MMP-2-deficiency significantly prolonged allograft survival time. Functioning allografts harvested from MMP-2-/- mice showed lower cellular infiltration and fibrosis than rejected allografts harvested from MMP-2+/+ mice at the same time. In contrast, MMP-9-deficiency significantly decreased allograft survival time. Functioning allografts harvested from MMP-9+/+ mice showed lower cellular infiltration and fibrosis than rejected allografts harvested from MMP-9-/- mice at the same time. MMP-2-/- recipients showed decreased T-cell alloreactivity mediated by a defect in dendritic cell stimulatory and T-cell responsive capacities. In contrast, MMP-9-/- recipients showed increased T-cell alloreactivity mediated by a significant increased in dendritic cell stimulatory and T-cell responsive capacities. These results indicate that MMP2 and MMP-9 play significantly different roles in the process of cardiac allograft rejection.

Animals↗
PubMed2006

Selective spatiotemporal induction of matrix metalloproteinase-2 and matrix metalloproteinase-9 transcription after myocardial infarction.

Myocardial remodeling after myocardial infarction (MI) is associated with increased levels of the matrix metalloproteinases (MMPs). Levels of two MMP species, MMP-2 and MMP-9, are increased after MI, and transgenic deletion of these MMPs attenuates post-MI left ventricular (LV) remodeling. This study characterized the spatiotemporal patterns of gene promoter induction for MMP-2 and MMP-9 after MI. MI was induced in transgenic mice in which the MMP-2 or MMP-9 promoter sequence was fused to the beta-galactosidase reporter, and reporter level was assayed up to 28 days after MI. Myocardial localization with respect to cellular sources of MMP-2 and MMP-9 promoter induction was examined. After MI, LV diameter increased by 70% (P < 0.05), consistent with LV remodeling. beta-Galactosidase staining in MMP-2 reporter mice was increased by 1 day after MI and increased further to 64 +/- 6% of LV epicardial area by 7 days after MI (P < 0.05). MMP-2 promoter activation occurred in fibroblasts and myofibroblasts in the MI region. In MMP-9 reporter mice, promoter induction was detected after 3 days and peaked at 7 days after MI (53 +/- 6%, P < 0.05) and was colocalized with inflammatory cells at the peri-infarct region. Although MMP-2 promoter activation was similarly distributed in the MI and border regions, activation of the MMP-9 promoter was highest at the border between the MI and remote regions. These unique findings visually demonstrated that activation of the MMP-2 and MMP-9 gene promoters occurs in a distinct spatial relation with reference to the MI region and changes in a characteristic time-dependent manner after MI.

Animals↗
PubMed1997

Tyrosine phosphorylation mediates ConA-induced membrane type 1-matrix metalloproteinase expression and matrix metalloproteinase-2 activation in MDA-MB-231 human breast carcinoma cells.

ConA-induced cell surface activation of pro-matrix metalloproteinase-2 (pro-MMP-2) by MDA-MB-231 human breast cancer cells is apparently mediated by up-regulation of membrane type 1 MMP (MT1-MMP) through transcriptional and posttranscriptional mechanisms. Here, we have explored the respective roles of cell surface clustering and protein tyrosine phosphorylation in the ConA-induction effects. Treatment with succinyl-ConA, a variant lacking significant clusterability, partially stimulated MT1-MMP mRNA and protein levels but did not induce MMP-2 activation, suggesting that clustering contributes to the transcriptional regulation by ConA but appears to be critical for the nontranscriptional component. We further found that genistein, an inhibitor of tyrosine phosphorylation, blocked ConA-induced pro-MMP-2 activation and ConA-induced MT1-MMP mRNA level in a dose-dependent manner, implicating tyrosine phosphorylation in the transcriptional aspect. This was confirmed by the dose-dependent promotion of pro-MMP-2 activation by sodium orthovanadate in the presence of suboptimal concentrations of ConA (7.5 microg/ml), with optimal effects seen at 25 microg/ml orthovanadate. Genistein did not inhibit the ConA potentiation of MMP-2 activation in MCF-7 cells, in which transfected MT1-MMP is driven by a heterologous promoter, supporting the major implication of phosphotyrosine in the transcriptional component of ConA regulation. These data describe a major signaling event upstream of MT1-MMP induction by ConA and set the stage for further analysis of the nontranscriptional component.

Concanavalin A↗
PubMed1994

Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques.

Dysregulated extracellular matrix (ECM) metabolism may contribute to vascular remodeling during the development and complication of human atherosclerotic lesions. We investigated the expression of matrix metalloproteinases (MMPs), a family of enzymes that degrade ECM components in human atherosclerotic plaques (n = 30) and in uninvolved arterial specimens (n = 11). We studied members of all three MMP classes (interstitial collagenase, MMP-1; gelatinases, MMP-2 and MMP-9; and stromelysin, MMP-3) and their endogenous inhibitors (TIMPs 1 and 2) by immunocytochemistry, zymography, and immunoprecipitation. Normal arteries stained uniformly for 72-kD gelatinase and TIMPs. In contrast, plaques' shoulders and regions of foam cell accumulation displayed locally increased expression of 92-kD gelatinase, stromelysin, and interstitial collagenase. However, the mere presence of MMP does not establish their catalytic capacity, as the zymogens lack activity, and TIMPs may block activated MMPs. All plaque extracts contained activated forms of gelatinases determined zymographically and by degradation of 3H-collagen type IV. To test directly whether atheromata actually contain active matrix-degrading enzymes in situ, we devised a method which allows the detection and microscopic localization of MMP enzymatic activity directly in tissue sections. In situ zymography revealed gelatinolytic and caseinolytic activity in frozen sections of atherosclerotic but not of uninvolved arterial tissues. The MMP inhibitors, EDTA and 1,10-phenanthroline, as well as recombinant TIMP-1, reduced these activities which colocalized with regions of increased immunoreactive MMP expression, i.e., the shoulders, core, and microvasculature of the plaques. Focal overexpression of activated MMP may promote destabilization and complication of atherosclerotic plaques and provide novel targets for therapeutic intervention.

Arteries↗