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MMP-9
Terms modified by MMP-9 Selected AbstractsSerum Iron and Matrix Metalloproteinase-9 Variations in Limbs Affected by Chronic Venous Disease and Venous Leg UlcersDERMATOLOGIC SURGERY, Issue 6 2005Paolo Zamboni MD Background. Severe chronic venous disease (CVD) is characterized by both dermal hemosiderin accumulation and matrix metalloproteinase (MMP) hyperactivation. The iron-driven pathway is one of the recognized mechanisms of MMP hyperactivation. Objective. To investigate the potential consequences of leg hemosiderin deposits on both iron metabolism and activation of MMPs. Methods. We contemporaneously assessed the following in the serum of the arm and ankle veins of 30 patients (C4,6) with CVD and 14 normal subjects: ferritin, transferrin, iron, percentage of transferrin iron binding capacity (%TIBC), and MMP-9. Optical microscopy examinations with Perls' staining of chronic wounds were also performed. Results. Histology consistently revealed iron deposits. Serum ferritin, iron, and %TIBC were significantly increased in the legs affected by severe CVD compared with the arm of the same subjects or the controls. In addition, iron and %TIBC were significantly elevated in the legs of ulcer patients. The rate of activation of MMP-9 was significantly elevated in CVD. Conclusions. The increased iron deposition in legs affected by CVD seems to be more instable in ulcer patients, leading to iron release in the serum of the affected leg. Our data suggest the iron-driven pathway as a further mechanism for MMP hyperexpression leading to tissue lesion. [source] MMP-2 contributes to the development of the mouse ventral prostate by impacting epithelial growth and morphogenesisDEVELOPMENTAL DYNAMICS, Issue 9 2010Alexandre Bruni-Cardoso Abstract Epithelial growth, branching, and canalization are important morphogenetic events of the rodent ventral prostate (VP) that take place during the first postnatal week. In this study, we evaluated the effect of knocking out MMP-2 (MMP-2,/,), by examining developmental and structural aspects of the VP in MMP-2,/, mice. Neonate (day 6) MMP-2,/, mice showed fewer epithelial tips, a lower epithelial cell proliferation rate, and also reticulin fiber accumulation. The VP of adult MMP-2,/, mice showed lower relative weight, smaller epithelial and smooth-muscle cell volume, and a larger amount of thicker reticulin fibers. No differences in cell proliferation or apoptotic index were noted between adult MMP-2,/, and wild-type mice. MMP-9 was found in the adult MMP-2,/,, but not in the wild-type. In conclusion, MMP-2 function is essential for the epithelial morphogenesis of the mouse VP, and expression of MMP-9 is not sufficient for acquisition of the normal adult histology. Developmental Dynamics 239:2386,2392, 2010. © 2010 Wiley-Liss, Inc. [source] Expression profiles of the duplicated matrix metalloproteinase-9 genes suggest their different roles in apoptosis of larval intestinal epithelial cells during Xenopus laevis metamorphosisDEVELOPMENTAL DYNAMICS, Issue 8 2007Takashi Hasebe Abstract Matrix metalloproteinases (MMPs) play a pivotal role in development and/or pathogenesis through degrading extracellular matrix (ECM) components. We have previously shown that Xenopus MMP-9 gene is duplicated. To assess possible roles of MMP-9 and MMP-9TH in X. laevis intestinal remodeling, we here analyzed their expression profiles by in situ hybridization and show that their expression is transiently up-regulated during thyroid hormone-dependent metamorphosis. Of interest, MMP-9TH mRNA is strictly localized in the connective tissue and most highly expressed just beneath the larval epithelium that begins to undergo apoptosis. On the other hand, cells expressing MMP-9 mRNA become first detectable in the connective tissue and then, after the start of epithelial apoptosis, also in the larval epithelium. These results strongly suggest that MMP-9TH is responsible in the larval epithelial apoptosis through degrading ECM components in the basal lamina, whereas MMP-9 is involved in the removal of dying epithelial cells during amphibian intestinal remodeling. Developmental Dynamics 236:2338,2345, 2007. © 2007 Wiley-Liss, Inc. [source] Matrix metalloproteinases mediate the dismantling of mesenchymal structures in the tadpole tail during thyroid hormone-induced tail resorptionDEVELOPMENTAL DYNAMICS, Issue 3 2002Jae-Chang Jung Abstract It has been suggested that a family of tissue remodelling enzymes called matrix metalloproteinases (MMPs) play a causal role in the process of tail resorption during thyroid hormone-induced metamorphosis of the anuran tadpole; however, this hypothesis has never been directly substantiated. We cloned two new Xenopus MMPs, gelatinase A (MMP-2) and MT3-MMP (MMP-16), and the MMP inhibitor TIMP-2. These clones were used along with several others to perform a comprehensive expression study. We show that all MMPs and TIMP-2 are dramatically induced in the resorbing tail during spontaneous metamorphosis and are spatially coexpressed, primarily in the remodelling mesenchymal tissues. By Northern blotting, we show that all the examined MMPs/TIMP-2 are also induced by treatment of organ-cultured tails with thyroid hormone (T3). Using the organ culture model, we provide the first direct evidence that MMPs are required for T3 -induced tail resorption by showing that a synthetic inhibitor of MMP activity/expression can specifically retard the resorption process. By gelatin zymography, we also show T3 induction of a fifth MMP, preliminarily identified as gelatinase B (GelB; MMP-9). Moreover, T3 not only induces MMP/TIMP expression but also MMP activation, and we provide evidence that TIMP-2 participates in the latter process. These findings suggest that MMPs and TIMPs act in concert to effect the dismantling of mesenchymal structures during T3 -induced metamorphic tadpole tail resorption. © 2002 Wiley-Liss, Inc. [source] Maternal hypoxia increases the activity of MMPs and decreases the expression of TIMPs in the brain of neonatal ratsDEVELOPMENTAL NEUROBIOLOGY, Issue 3 2010Wenni Tong Abstract A recent study has shown that increased activity of matrix metalloproteinases-2 and metalloproteinases-9 (MMP-2 and MMP-9) has detrimental effect on the brain after neonatal hypoxia. The present study determined the effect of maternal hypoxia on neuronal survivability and the activity of MMP-2 and MMP-9, as well as the expression of tissue inhibitors of metalloproteinase 1 and 2 (TIMP-1 and TIMP-2) in the brain of neonatal rats. Pregnant rats were exposed to 10.5% oxygen for 6 days from the gestation day 15 to day 21. Pups were sacrificed at day 0, 4, 7, 14, and 21 after birth. Body weight and brain weight of the pups were measured at each time point. The activity of MMP-2 and MMP-9 and the protein abundance of TIMP-1 and TIMP-2 were determined by zymography and Western blotting, respectively. The tissue distribution of MMPs was examined by immunofluorescence staining. The neuronal death was detected by Nissl staining. Maternal hypoxia caused significant decreases in body and brain size, increased activity of MMP-2 at day 0, and increased MMP-9 at day 0 and 4. The increased activity of the MMPs was accompanied by an overall tendency towards a reduced expression of TIMPs at all ages with the significance observed for TIMPs at day 0, 4, and 7. Immunofluorescence analysis showed an increased expression of MMP-2, MMP-9 in the hippocampus at day 0 and 4. Nissl staining revealed significant cell death in the hippocampus at day 0, 4, and 7. Functional tests showed worse neurobehavioral outcomes in the hypoxic animals. © 2009 Wiley Periodicals, Inc. Develop Neurobiol 2010 [source] Peripheral blood level alterations of TIMP-1, MMP-2 and MMP-9 in patients with Type 1 diabetesDIABETIC MEDICINE, Issue 10 2001P. R. Maxwell Abstract Aim To determine the plasma levels of enzymes and inhibitors involved in extracellular matrix turnover in patients with Type 1 diabetes with normal renal function. Methods Plasma levels of matrix metalloproteinases 2 and 9 (MMP-2, MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were measured in 43 Type 1 diabetic subjects and age- and sex-matched controls. Results No significant difference in plasma MMP-2 between diabetic patients and controls was observed. MMP-9 was detected in the plasma of 15 diabetic patients (35%), but undetectable in all control subjects (P < 0.015). Plasma TIMP-1 concentrations were significantly elevated (P < 0.001) in diabetic patients compared to controls. There was no correlation observed between MMP-2, MMP-9 and TIMP-1 and similarly between MMP-2, MMP-9 and TIMP-1 and age, duration of diabetes, blood pressure and glycated haemoglobin (HbA1c). Conclusions This study has demonstrated alterations in several plasma extracellular matrix modulators in the absence of significant vascular disease. Diabet. Med. 18, 777,780 (2001) [source] Peptide-doxorubicin conjugates specifically degraded by matrix metalloproteinases expressed from tumorDRUG DEVELOPMENT RESEARCH, Issue 5 2006Gee Young Lee Abstract Specific peptide-doxorubicin conjugates were developed for targeting matrix metalloproteinases (MMPs) expressed from tumors. The peptide-doxorubicin conjugates were designed to be cleaved by MMP-2 and MMP-9 in order that doxorubicin or the active form that acts as an anticancer agent was released free from the peptide fragment at the tumor site. Three types of peptide-doxorubicin conjugates were synthesized using the peptides: GPLG (Gly-Pro-Leu-Gly), GPLGV (Gly-Pro-Leu-Gly-Val), and GPLGPAG (Gly-Pro-Leu-Gly-Pro-Ala-Gly). The synthesized peptide-doxorubicin conjugates were characterized for their degradation behavior and bioactivity in vitro, and their antitumoral activity was assessed using the Lewis lung carcinoma (LLC) model, which expresses MMP-2 and MMP-9. After incubation with active MMP-2 for 24,h, GPLG-doxorubicin was barely degraded, whereas GPLGV-doxorubicin and GPLGPAG-doxorubicin were considerably degraded by active MMP-2. Consequently, all peptide-doxorubicin conjugates had significantly low cytotoxicity compared to doxorubicin, but tumor growth suppression was exhibited only by GPLGV-doxorubicin and GPLGPAG-doxorubicin. The tumor growth suppression by the two conjugates was higher compared to control, although it did not exceed the suppression level shown by doxorubicin. The low toxicity exhibited by peptide-doxorubicin conjugates resulted in only slight body weight loss in mice, whereas doxorubicin greatly reduced body weight and induced severe side effects. Therefore, we propose MMPs-specific peptide-doxorubicin conjugates in targeting anti-cancer drug delivery that could reduce systemic toxicities. Drug Dev. Res. 67:438,447, 2006. © 2006 Wiley-Liss, Inc. [source] DIASTOLIC DYSFUNCTION IN HYPERTENSIVES AS ASSESSED BY TISSUE DOPPLER; RELATION TO MATRIX METALLOPROTEINASESECHOCARDIOGRAPHY, Issue 5 2004S. Nadar Objectives: To assess the severity of diastolic dysfunction in hypertensive patients as compared to normal controls and correlate it with plasma matrix metalloproteinases (MMPs). Methods: 52 patients with controlled hypertension (HT) (38 male, age 57+ 11 yrs) and 24 normotensive controls 15 male, mean age 53+ 12 years) had tissue doppler echocardiography to assess diastolic dysfunction (e, and e,/e ratios). They also had plasma MMP-9 and TIMP-1 measured. Results: The HT patients had significantly lower e, and higher e,/e ratios as compared to normotensive controls. They also had higher MMP-9 and TIMP-1 values. There was a significant inverese correlation between MMP-9 and TIMP-1 with e, and a significant positive correlation between the MMPs and e,/e ratio. THe e/a ratios as assessed by pulse wave doppler were also higher in the controls than the hypertensive patients suggesting abnormal diastolic function. Conclusions: There is significant diastolic dysfunction even in controlled hypertensives which can be assessed by tissue doppler. This newer technique compares favourably with established methods such as e/a ratio. The tissue doppler indices also correlate well with abnormalities in the matrix metalloproteinases suggesting that abnormal matrix turnover is responsible for the diastolic dysfunction. [source] Plasma matrix metalloproteinase-3 level is an independent prognostic factor in stable coronary artery diseaseEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 9 2005T. C. Wu Abstract Background, Recent evidence suggests the important role of matrix metalloproteinases (MMPs) in the progression of atherosclerosis and development of clinical events. We assessed the prognostic value of different plasma MMPs in patients with stable coronary artery disease (CAD). Materials and methods, A total of 165 consecutive nondiabetic patients with angiographically significant CAD (n = 150) or normal coronary angiograms despite exercise-induced myocardial ischemia (cardiac syndrome X, n = 15) and 17 normal subjects were evaluated. In each subject, plasma inflammatory markers including high sensitivity C-reactive protein (hsCRP) and MMP-2, 3 and 9 were measured. In CAD patients, major cardiovascular events including cardiac death, nonfatal myocardial infarction, unscheduled coronary revascularization and hospitalization as a result of unstable angina were prospectively followed up for more than 6 months. Results, Plasma levels of MMPs were significantly higher in CAD patients than in those with cardiac syndrome X and in normal subjects (MMP-2: 914·76 ± 13·20 vs. 830·79 ± 31·95 vs. 783·08 ± 28·40 ng mL,1, P = 0·002; MMP-3: 129·59 ± 4·21 vs. 116·86 ± 8·09 vs. 91·71 ± 9·55 ng mL,1, P = 0·011; MMP-9: 31·42 ± 2·84 vs. 11·40 ± 5·49 vs. 6·71 ± 2·89 ng mL,1, P = 0·006). In CAD patients, there were 48 major cardiovascular events during a mean follow-up period of 17·74 ± 0·85 months. The numbers of diseased vessels (HR = 2·19, 95% CI 1·20,1·02, P = 0·011), plasma hsCRP (HR = 2·21, 95% CI 1·18,4·11, P = 0·013) and MMP-3 level (HR = 2·46, 95% CI = 1·15,5·28, P = 0·021) were associated with the development of cardiovascular events. However, only the plasma MMP-3 level was an independent predictor of the adverse events in CAD patients (HR = 2·47, 95% CI 1·10,5·54, P = 0·028). Conclusions, Plasma MMP levels were increased in CAD patients. Plasma MMP-3 level, rather than hsCRP, was an independent prognostic marker for future cardiovascular events, suggesting its potential role in risk stratification and clinical management of stable CAD. [source] Association of serum sialic acid and MMP-9 with lipids and inflammatory markersEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2 2000Kalela Background Inflammation of the arterial wall has emerged to be an important contributor to the process of atherosclerosis, the major cause of coronary heart disease. Several factors are currently under investigation as inflammatory markers of atherosclerosis. Serum sialic acid and matrix metalloproteinase-9 may provide such markers. We studied their association with the lipid profile and with the inflammatory markers C-reactive protein and leukocyte count in a clinically healthy population of men. Materials and methods Cardiovascular risk-related laboratory tests were carried out in 65 consecutive male employees in connection with an occupational health survey in 1996. The subjects were divided into tertiles on the basis of serum sialic acid or matrix metalloproteinase-9 concentration. Results In a stepwise polychotomous logistic regression model adjusting for coronary heart disease risk factors, serum sialic acid concentration was not associated with markers of inflammation but rather with the lipid risk factors of atherosclerosis: inversely with HDL cholesterol (OR = 0.081, 95% CI 0.0068,0.97) and positively with total cholesterol (OR = 2.4, 95% CI 1,5.6). Matrix metalloproteinase-9 levels had a significant positive correlation with the leukocyte count (OR = 2.3, 95% CI 1.4,4). Conclusions Serum sialic acid does not appear to be an indicator of inflammation but is somehow connected with the level of total and HDL cholesterol. Serum matrix metalloproteinase-9 may provide a useful marker of inflammation because it correlates with the leukocyte count and is not associated with the lipid profile. [source] Hypoxia suppresses the production of matrix metalloproteinases and the migration of humanmonocyte-derived dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2005Wenli Zhao Abstract As most solid tumors are hypoxic, dendritic cells (DC) in solid tumors are also exposed to hypoxia. While many adaptation responses of tumor cells to hypoxia are known, it is yet to be determined how hypoxia affects the functions of DC. To explore the effects of hypoxia on the functions of DC, we compared the expression of surface markers, cytokines, chemokine receptors and matrix metalloproteinases (MMP) of human monocyte-derived DC (hmDC) differentiated under hypoxia to those differentiated under normoxia. Both groups of hmDC expressed similar levels of surface markers and cytokines. However, expression of MMP-9 and membrane type-1-MMP, as well as migrating activity, was significantly suppressed in hmDC differentiated under hypoxia compared with their normoxia counterparts. We also demonstrated that trichostatin A restored the production of MMP-9 in hmDC, under hypoxia. Collectively, our findings show that a hypoxic microenvironment suppresses the production of MMP in hmDC, most probably through the deacetylation of promoter regions of MMP, thus suppressing the migrating activity of hmDC. Our results suggest that the hypoxic microenvironment in solid tumor tissues may suppress the function of DC. [source] The effects of natalizumab on inflammatory mediators in multiple sclerosis: prospects for treatment-sensitive biomarkersEUROPEAN JOURNAL OF NEUROLOGY, Issue 4 2009M. Khademi Background:, Natalizumab affects systemic cytokine expressions and clinical course in relapsing,remitting multiple sclerosis (RRMS). We analyzed levels of inflammatory cytokines in cerebrospinal fluid (CSF) cells and peripheral blood mononuclear cells (PBMCs), levels of matrix metalloproteinase (MMP)-9 and osteopontin (OPN) in CSF, and clinical outcome measures in 22 natalizumab-treated RRMS patients. Methods:, mRNA levels of cytokines in cells were detected with real-time RT-PCR. Protein levels of OPN and MMP-9 were measured by ELISA. Results:, Natalizumab reduced CSF cell counts (P < 0.0001). Tumor necrosis factor (TNF) and interferon-, (IFN-,) mRNAs were significantly increased in PBMCs. In contrast, expressions of IFN-, and interleukin (IL)-23 were decreased but IL-10 increased in the CSF cells. OPN and MMP-9 were reduced in the CSF. Patients being in remission at baseline showed the same deviations of mediators as those in relapse after natalizumab treatment. The open label clinical outcome measures were either stable or improved during therapy. Conclusions:, Natalizumab attenuates pro-inflammatory mediators intrathecally and the reduced pro-inflammatory milieu may allow increased production of the anti-inflammatory mediator IL-10. The increased systemic cytokines may impede the improvement of certain clinical measures like fatigue. The affected mediators seem to be sensitive to an immune-modifying treatment which could be used as biomarkers for this therapy. [source] Metalloproteinase expression in normal and malignant oral keratinocytes: stimulation of MMP-2 and -9 by scatter factorEUROPEAN JOURNAL OF ORAL SCIENCES, Issue 4 2000J. H. Bennett Matrix metalloproteinases (MMPs) are Zn2+ dependent proteases produced by a variety of cell types. They have a fundamental role in tissue remodelling, tumour invasion and metastasis. Scatter factor (SF), secreted by fibroblasts, has a paracrine action on epithelial cells and binds the trans-membrane c-met receptor inducing loss of adhesion, cell motility and invasiveness in vitro. The purpose of this study was to test if SF can regulate the production of MMPs by epithelial cells. Supernatants from oral squamous cell carcinoma-derived cells (H375 and H376), a human keratinocyte line (UP), and primary cultures of oral mucosal keratinocytes, grown in the presence or absence of SF, were analysed using 0.1% gelatin zymography. MMPs were characterised by comparison with human recombinant enzymes and by the use of specific inhibitors. Oral mucosal keratinocytes, UP, and H357 cells expressed MMP-2 and MMP-9, whilst H376 cells only expressed MMP-2. SF increased the expression of MMP-9 in UP and MMP-2 in H376 supernatants. Both MMP-2 and MMP-9 activity were increased in H357 and normal keratinocyte supernatants. This could be blocked using a human recombinant anti-SF antibody. In all epithelial lines tested, c-Met, the cell surface receptor for SF, could be detected. The results indicate that SF stimulates MMP expression in UP, H376, H357, and normal oral mucosal cells and points to a role for SF in the regulation of oral keratinocyte behaviour in wound healing and neoplasia. [source] In vitro induction of matrix metalloproteinase-2 and matrix metalloproteinase-9 expression in keratinocytes by boron and manganeseEXPERIMENTAL DERMATOLOGY, Issue 8 2004Nathalie Chebassier Abstract:, 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 µg/ml or manganese at 0.2 µg/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. [source] A link between neutrophils and chronic disease manifestations of Chlamydia muridarum urogenital infection of miceFEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 1 2010Hyo Y. Lee Abstract Vigorous acute inflammatory responses accompany Chlamydia muridarum infections in mice and are positively correlated with adverse urogenital and respiratory tract infection outcomes in the mouse model. Thus, we tested the hypothesis that neutrophils induce an acute inflammatory insult that, in the repair phase, leads to the chronic sequelae of hydrosalpinx , a surrogate marker of infertility in the mouse model. To this end, we induced neutropenia in mice using a neutrophil-depleting monoclonal antibody during acute phases of C. muridarum urogenital infection only (days 2,21 postinfection). To prove induced neutropenia, peripheral blood was monitored for neutrophils during the treatment regimen. Neutropenic mice had a similar infection course as control mice, but had significantly reduced levels of certain histopathological parameters, reduced production of matrix metalloproteinase-9 (MMP-9) and reduced rates of hydrosalpinx following resolution of the infection. We conclude that neutrophils are a major source of MMP-9, a previously proved pathological factor in this model. Further, we conclude that acute inflammation in the form of neutrophils and neutrophil activation products are at least partially responsible for inducing the histological changes that ultimately result in fibrosis and infertility in the mouse model of chlamydial upper genital tract disease. [source] Secretion of matrix metalloproteinase-9 by the proinflammatory cytokine, IL-1,: a role for the dual signalling pathways, Akt and ErkGENES TO CELLS, Issue 6 2003A. R. M. Ruhul Amin Background: Matrix metalloproteinases including MMP-9 mediate matrix destruction during chronic inflammatory diseases such as arthritis and atherosclerosis. MMP-9 up-regulation by inflammatory cytokines involve interactions between several transcription factors including activator protein-1 and NF,B. The upstream regulatory pathways are less well understood. Results: To search for the mechanism of tissue destruction in the process of inflammatory disorders, we investigated the signalling pathway critical for the activation of MMP-9 expression and secretion by IL-1,. Treatment of Balb 3T3 cells with IL-1, activated MMP-9 transcription and subsequent secretion in a time- and dose-dependent manner. Concomitantly, IL-1, treatment of cells activated phosphorylation of Akt, Erk and p38. Treatment of cells with either LY294002, a PI3K inhibitor, or expression of a dominant negative form of Akt drastically suppressed the IL-1,-dependent secretion of MMP-9. Pretreatment of cells with a MEK1 inhibitor, U0126, also strongly inhibited IL-1,-dependent secretion of MMP-9. In contrast, pre-treatment with a specific p38 kinase inhibitor, SB203580, had no effect on IL-1,-dependent secretion of MMP-9. In addition, cells expressing constitutively active form of Akt or MEK1 showed no clear activation of MMP-9 secretion, whereas these cells responded well to IL-1, treatment. However, co-transfection of cells with both active Akt and MEK1 was sufficient to induce MMP-9 secretion without stimulation with IL-1,. Conclusion: Taken together, our results suggest that IL-1, stimulation of cells activates MMP-9 secretion by the activation of the dual signalling pathways, the PI3K-Akt and MEK1-Erk and constitutive activation of these pathways were sufficient to induce MMP-9 secretion. [source] Oxidized low-density lipoprotein induces matrix metalloproteinase-9 expression via a p42/p44 and JNK-dependent AP-1 pathway in brain astrocytesGLIA, Issue 1 2009Hui-Hsin Wang Abstract Upregulation of matrix metalloproteinases (MMPs), especially MMP-9, by oxidized low-density lipoprotein (oxLDL) is implicated in many inflammatory diseases including brain injury. However, the signaling mechanisms underlying oxLDL-induced MMP-9 expression in astrocytes largely remain unknown. Here we report that oxLDL induces expression of proMMP-9 via a MAPK-dependent AP-1 activation in rat brain astrocyte (RBA)-1 cells. Results revealed by gelatin zymography, RT-PCR, and Western blotting analyses showed that oxLDL-induced proMMP-9 gene expression was mediated through Akt, JNK1/2, and p42/p44 MAPK phosphorylation in RBA-1 cells. These responses were attenuated by inhibitors of PI3K (LY294002), JNK (SP600125), and p42/p44 MAPK (PD98059), or transfection with dominant negative mutants and short hairpin RNA. Moreover, we demonstrated that AP-1 (i.e., c-Fos/c-Jun) is crucial for oxLDL-induced proMMP-9 expression which was attenuated by pretreatment with AP-1 inhibitor (curcumin). The regulation of MMP-9 gene transcription by AP-1 was confirmed by oxLDL-stimulated MMP-9 luciferase activity which was totally lost in cells transfected with the AP-1 binding site-mutated MMP-9 promoter construct (mt-AP1-MMP-9). These results suggested that oxLDL-induced proMMP-9 expression is mediated through PI3K/Akt, JNK1/2, and p42/p44 MAPK leading to AP-1 activation. Understanding the regulatory mechanisms underlying oxLDL-induced MMP-9 expression in astrocytes might provide a new therapeutic strategy of brain injuries and diseases. © 2008 Wiley-Liss, Inc. [source] Decreased hepatic nitric oxide production contributes to the development of rat sinusoidal obstruction syndromeHEPATOLOGY, Issue 4 2003Laurie D. Deleve M.D., Ph.D. This study examined the role of decreased nitric oxide (NO) in the microcirculatory obstruction of hepatic sinusoidal obstruction syndrome (SOS). SOS was induced in rats with monocrotaline. Monocrotaline caused hepatic vein NO to decrease by 30% at 24 hours and by 70% at 72 hours; this decrease persisted throughout late SOS. NG -nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, exacerbated monocrotaline toxicity, whereas V-PYRRO/NO, a liver-selective NO donor prodrug, restored NO levels, preserved sinusoidal endothelial cell (SEC) integrity and sinusoidal perfusion as assessed by in vivo microscopy and electron microscopy, and prevented clinical and histologic evidence of SOS. NO production in vitro by SEC and Kupffer cells, the 2 major liver cell sources of NO, decreases largely in parallel with loss of cell viability after exposure to monocrotaline. Increased matrix metalloproteinase (MMP) activity increases early on in SOS and this increase in activity has been implicated in initiating SOS. Infusion of V-PYRRO-NO prevented the monocrotaline-induced increase in MMP-9. In conclusion, decreased hepatic NO production contributes to the development of SOS. Infusion of an NO donor preserves SEC integrity and prevents development of SOS. These findings show that a decrease in NO contributes to SOS by allowing up-regulation of MMP activity, loss of sinusoidal integrity, and subsequent disruption of sinusoidal perfusion. (Hepatology 2003;38:900,908). [source] Lipoxin A4 inhibited hepatocyte growth factor-induced invasion of human hepatoma cellsHEPATOLOGY RESEARCH, Issue 9 2009Xiao-Yan Zhou Aim:, Inflammation is a critical component of tumor progression. Lipoxin A4 (LXA4) has been approved for potent anti-inflammatory properties. Recently, it was reported that LXA4 repressed the expression and activity of cyclooxygenase-2 (COX-2), which is essential for invasion. However, there are few reports dealing with its effects on cancer. To explore whether LXA4 regulate invasion, the effects of LXA4 and its receptor agonist BML-111 on hepatocyte growth factor (HGF)-induced invasion of hepatoma cells and the possible mechanisms were researched. Methods:, Lipoxin A4 receptor (ALX) expression in HepG2 cells were measured through reverse transcription polymerase chain reaction and western blot. Cytotoxicity of LXA4 and BML-111 to HepG2 cells was detected by MTT and (3H)-TdR incorporation assay. Cell migration and invasion assays were performed using a Boyden chemotaxis chamber. COX-2 expression was detected by real-time polymerase chain reaction and western blot, respectively. Moreover, the expressions of matrix metalloproteinases (MMP)-2, MMP-9, I,B, and nuclear factor-,B (NF-,B) p65 were observed via western blot, and NF-,B transcriptional activity was tested by transfections and luciferase activities assay. Results:, ALX expression was detected in HepG2 cells, and suitable concentrations of LXA4 and BML-111 had no cytotoxicity to cells. LXA4 and BML-111 inhibited HGF-induced migration and invasion; downregulated COX-2, MMP-2 and -9; restrained HGF-induced I,B, degradation, NF-,B translocation and the transcriptional activity of NF-,B in HepG2 cells. Furthermore, exogenous PGE2 could reverse the inhibitory effects of LXA4 also BML-111 on HGF-induced invasion and migration partially. Conclusion:, LXA4 inhibited HGF-induced invasion of HepG2 cells through NF-,B/COX-2 signaling pathway partially. [source] Expression of matrix metalloproteinases MMP-2, MMP-9 and their tissue inhibitors TIMP-1 and TIMP-2 in the epithelium and stroma of salivary gland pleomorphic adenomasHISTOPATHOLOGY, Issue 3 2009Xiaojun Zhang Aims:, The balance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) is involved in the morphogenesis of normal salivary gland as well as in the mechanisms of tumour invasion and metastasis. The role of MMPs and TIMPs in pleomorphic adenoma has not been elucidated sufficiently. Our aim was to analyse the mRNA and protein expression of MMP-2, MMP-9, TIMP-1 and TIMP-2 in the epithelium and stroma of pleomorphic adenoma and to evaluate their roles. Methods and results:, In each sample from six patients, cells from the epithelium and stroma were obtained by laser microdissection. The mRNA expression of MMPs and TIMPs was determined by real-time quantitative reverse transcriptase-polymerase chain reaction and protein expression was confirmed by immunohistochemistry. Results showed that mRNA expression of MMPs and TIMPs was significantly higher in stroma than in epithelium in most patients. MMPs and TIMPs were immunoreactive mainly in epithelium rather than in stroma. Conclusions:, Our results provide preliminary evidence that stromal myoepithelium may be the primary source of MMPs and that the stroma has the potential to play a more important role than ductal epithelium in biological behaviour of pleomorphic adenomas. These findings seem worthy of further investigation. [source] Enhanced expression of MMP-7 and MMP-13 in inflammatory bowel disease: A precancerous potential?INFLAMMATORY BOWEL DISEASES, Issue 11 2006Dr. Timo Rath PhD Abstract Matrix metalloproteinases (MMPs) are responsible for the turnover and degradation of extracellular matrix. They play a crucial role in the growth and migration of colorectal carcinoma cells. Colorectal carcinomas are characterized by enhanced expression of MMP-2, MMP-9, MMP-7, and MMP-13. The aim of this study was to determine the expression levels of MMP-2, MMP-9, MMP-7, MMP-13, and MMP-14 and their specific inhibitor TIMP-1 in inflammatory bowel diseases and precancerous lesions of the colon, i.e., Crohn's disease and ulcerative colitis, and in adenomatous polyps (APs) for comparison. Biopsy samples of pathological and healthy tissue were obtained from 40 patients with inflammatory bowel disease (ulcerative colitis, n = 17; Crohn's disease, n = 23) and from 19 patients with APs. mRNA was measured by quantitative real-time polymerase chain reaction to study MMP and TIMP-1 gene expression in both pathological and normal mucosal specimens. For MMP-2, MMP-9, and TIMP-1, protein expression also was quantified with sandwich enzyme-linked immunosorbent assay. In biopsy specimens of Crohn's disease and ulcerative colitis, significantly increased levels of MMP-2, MMP-7, and MMP-13 mRNA were found. MMP-2 and MMP-9 showed enhanced secretion on the protein level. AP revealed an increased transcription of MMP-7 and MMP-13 genes. MMP-14 mRNA was decreased in APs. MMPs, especially MMP-7 and MMP-13, which are expressed primarily on the tumor cell surface, are elevated in inflammatory bowel disease, which may have more chance to evolve into malignancy than normal tissue. In APs, increased expression of MMP-7 and MMP-13 may serve as an early indicator for colorectal carcinogenesis. [source] Combined effect of the finasteride and doxazosin on rat ventral prostate morphology and physiologyINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 3 2010Luis A. Justulin Jr Summary Finasteride (Fin) and Doxazosin (Dox), alone or in combination, have been widely used in treatment of benign prostatic hyperplasia (BPH) symptoms and recently have been suggested as potential drugs for prostate cancer (PCa)prevention and treatment. However, little is known about the effects of the combination therapy on prostate tissue morphology, physiology and matrix metalloproteinases (MMPs) activity, a special set of enzymes closely related to PCa progression and metastasis. In this study, adult Wistar rats were treated with Fin + Dox (25 mg/kg per day) and the ventral prostate (VP) was excised at days 3 and 30 of treatment to evaluate morphology, cell proliferation, death, transforming growth factor-beta1 (TGF-,1) protein expression, MMP-2, MMP-9 activities and MMP-2, MMP-9, TIMP-1 and TIMP-2 mRNA expression. Fin + Dox treatment induced a transient increase in testosterone (T) plasma concentration and a permanent reduction in dihydrotestosterone (DHT). The VP and epithelial cell proliferation were reduced and the stromal collagen fibre volume fraction and apoptosis of the epithelial cell were increased. Fin + Dox treatment also increased the TGF-,1 immunoreaction in the epithelium and in the stroma. The mRNAs for MMP-2, TIMPs-1 and -2 expressions after 30 days of treatment were decreased. The mRNA for MMP-9 was not detected in any of the groups analysed. Fin + Dox treatment for 30 days promoted a decrease in gelatinolytic activity of MMP-2 and an increase in MMP-9. In conclusion, combined treatment with Fin and Dox interferes in the epithelial cell behaviour and in the MMPs activity, potentially via TGF-,1-mediated and androgen pathways. Our results contribute to a better understanding of the clinical data and also of the molecular mechanisms behind isolated or combined Fin and Dox long-term treatment. [source] Finasteride treatment alters MMP-2 and -9 gene expression and activity in the rat ventral prostateINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 1 2010Flávia K. Delella Summary The safety of using finasteride as a prevention of prostate cancer is still under debate. In this study, we investigated the effects of finasteride on the location, gene expression and activities of matrix metalloproteinases -2 and -9, which are involved in the degradation of extracellular matrix components during tissue remodelling and prostate cancer progression, invasion and metastasis. Ventral prostates (VP) from Wistar rats treated with finasteride (25 mg/kg/day) for 7 and 30 days and age-matched controls were evaluated using histology, immunohistochemistry, semi-quantitative RT-PCR and gelatin zymography. Finasteride treatment reduced the epithelial immunostaining of MMP-2 but increased MMP-9 immunostaining in the epithelial cells and in the stroma. The mRNA expression of both MMP-2 and MMP-9 were significantly increased on day 7 of finasteride treatment, mainly for MMP-9 and returned to the control levels by day 30. However, gelatin zymography showed that MMP-9 activity was significantly increased on day 7 of finasteride treatment and remained elevated on day 30 (p < 0.05), while MMP-2 activity was reduced after 30 days of treatment. Finasteride increases MMP-9 and reduces MMP-2 activities in the prostate, which may affect negatively and positively both normal and tumoural prostatic cell behaviour during the treatment. Studies on expression of MMPs in the prostate during different androgen manipulation or cancer chemoprevention strategies can contribute to understand the tissue's overall response and clinical data. [source] Monocyte chemoattractant protein-1 (MCP-1)/CCL2 secreted by hepatic myofibroblasts promotes migration and invasion of human hepatoma cellsINTERNATIONAL JOURNAL OF CANCER, Issue 5 2010Maylis Dagouassat Abstract The aim of our study was to investigate whether myofibroblasts and the chemokine monocyte chemoattractant protein-1 (MCP-1)/CCL2 may play a role in hepatocellular carcinoma progression. We observed that hepatic myofibroblast LI90 cells express MCP-1/CCL2 mRNA and secrete this chemokine. Moreover, myofibroblast LI90 cell-conditioned medium (LI90-CM) induces human hepatoma Huh7 cell migration and invasion. These effects are strongly reduced when a MCP-1/CCL2-depleted LI90-CM was used. We showed that MCP-1/CCL2 induces Huh7 cell migration and invasion through its G-protein,coupled receptor CCR2 and, to a lesser extent, through CCR1 only at high MCP-1/CCL2 concentrations. MCP-1/CCL2's chemotactic activities rely on tyrosine phosphorylation of focal adhesion components and depend on matrix metalloproteinase (MMP)-2 and MMP-9. Furthermore, we observed that Huh7 cell migration and invasion induced by the chemokine are strongly inhibited by heparin, by ,-D-xyloside treatment of cells and by anti-syndecan-1 and -4 antibodies. Finally, we developed a 3-dimensional coculture model of myofibroblast LI90 and Huh7 cells and demonstrated that MCP-1/CCL2 and its membrane partners, CCR1 and CCR2, may be involved in the formation of mixed hepatoma-myofibroblast spheroids. In conclusion, our data show that human liver myofibroblasts act on hepatoma cells in a paracrine manner to increase their invasiveness and suggest that myofibroblast-derived MCP-1/CCL2 could be involved in the pathogenesis of hepatocellular carcinoma. [source] Active MMP-2 effectively identifies the presence of colorectal cancerINTERNATIONAL JOURNAL OF CANCER, Issue 12 2009Mary Jo Murnane Abstract Fully active MMP-2 is expressed at such low levels in human tissues that studies often fail to confirm its value as a cancer marker despite strong associations with malignancy. Our study utilized careful extraction, accurate activity measurements, standardization to purified controls and a new statistical metric to determine whether active MMP-2 is an effective indicator of colorectal cancer compared to pro-MMP-2 or pro-MMP-9. MMP-2 and MMP-9 activities were analyzed in matched normal and cancer samples from 269 patients by gelatin zymography, computer-assisted image analysis, serial dilutions of strong samples and standardization to controls. An index of effect size was designed for comparative evaluation of active MMP-2, pro-MMP-2 and pro-MMP-9 activities. For each gelatinase, mean activity and protein levels/mg soluble protein in normal mucosa and colorectal cancer were calculated for the first time with respect to commercial standards. Active MMP-2 activity, detected in 99% of colorectal cancers, was higher in 95% of cancers (on average 10-fold) than in normal mucosa. Levels of pro-MMP-2 and pro-MMP-9, but not active MMP-9, activities were also significantly higher in cancers versus normal. However, active MMP-2 activity provided the most effective test for the presence of cancer (p < 0.0.0001) with an effect size statistically significantly larger than for either pro-MMP-2 or pro-MMP-9. Receiver operating characteristic (ROC) curves demonstrated that a cut-off for active MMP-2 of >44 SDU activity/mg soluble protein (>180 pg/mg), which is three times mean normal levels, would permit detection of colorectal cancer with an estimated sensitivity of 84% and estimated specificity of 93%. © 2009 UICC [source] Distinct progression-associated expression of tumor and stromal MMPs in HaCaT skin SCCs correlates with onset of invasionINTERNATIONAL JOURNAL OF CANCER, Issue 10 2009Silvia Vosseler Abstract Matrix metalloproteinases (MMPs) are critically involved in tumor invasion and metastasis. However, failure of broad spectrum MMP inhibitors in clinical trials emphasizes the need for detailed analyses of the specific role of different MMPs in tumor malignancy. Using HaCaT-keratinocyte clones representing distinct stages in skin squamous cell carcinoma (SCC) progression, we demonstrate the expression of specific tumor and stroma-derived MMPs with the onset and maintenance of tumor invasion. Although MMP-9-positive leukocytes are present in benign and malignant tumor transplants at the onset of stromal activation and angiogenesis, mRNA expression of stroma-derived MMP-9 as well as MMP-2, ,13 and ,14 is exclusively found in enhanced malignant tumor transplants. Their expression initiates with the onset of invasion, whereas being absent in early noninvasive stages of malignant transplants. In addition, a high expression of tumor-derived MMP-1, ,2 and ,14 contributes to malignant and invasive tumor growth. However, stroma-derived MMP-3 is exclusively restricted to very late-stage invasive and malignant transplants. The functional contribution of these proteases to invasive growth is supported by the gelatinolytic activity in the tumor transplants that again initiates with the onset of invasive growth suggesting a crucial role of MMP-2, ,9, ,13 and ,14 for the establishment of a reactive stroma that promotes tumor invasion. These data demonstrate a complex cooperation of distinct tumor and stroma-derived MMPs in the establishment of malignant tumors and provide the basis for a more specific use of highly selective MMP inhibitors during distinct stages of tumor progression. © 2009 UICC [source] The hemopexin domain of MMP-9 inhibits angiogenesis and retards the growth of intracranial glioblastoma xenograft in nude miceINTERNATIONAL JOURNAL OF CANCER, Issue 2 2009Ravesanker Ezhilarasan Abstract Matrix Metalloproteinase-9 (MMP-9) consists of a prodomain, catalytic domain with 3 fibronectin-like type II modules and C-terminal hemopexin-like (PEX) domain. These domains play distinct roles in terms of proteolytic activity, substrate binding and interaction with inhibitors and receptors. To assess the potential of the MMP-9-PEX domain to interfere with tumor progression, we stably transfected human glioblastoma cells with an expression vector containing a cDNA sequence of the MMP-9-PEX. The selected clones exhibited decreased MMP-9 activity and reduced invasive capacity. We assessed how secretion of MMP-9-PEX by glioblastoma cells affects angiogenic capabilities of human microvascular endothelial cells (HMECs) in vitro. MMP-9-PEX conditioned medium treatment caused a reduction in migration of HMECs and inhibited capillary-like structure formation in association with suppression of vascular endothelial growth factor (VEGF) secretion and VEGF receptor-2 protein level. The suppression of HMECs survival by conditioned medium from MMP-9-PEX stable transfectants was associated with apoptosis induction characterized by an increase in cells with a sub-G0/G1 content, fragmentation of DNA, caspase-3, -8 and -9 activation and poly (ADP-ribose) polymerase (PARP) cleavage. A significant tumor growth inhibition was observed in intracranial implants of MMP-9-PEX stable transfectants in nude mice with attenuation of CD31 and MMP-9 protein expression. These results demonstrate that MMP-9-PEX inhibits angiogenic features of endothelial cells and retards intracranial glioblastoma growth. © 2008 Wiley-Liss, Inc. [source] IFN-, withdrawal after immunotherapy potentiates B16 melanoma invasion and metastasis by intensifying tumor integrin ,v,3 signalingINTERNATIONAL JOURNAL OF CANCER, Issue 3 2008Wei Gong Abstract Immunotherapy can effectively suppress tumor, yet complete tumor eradication occurs infrequently. The metastatic potential of remnant tumor cells after immunotherapy and the underlying mechanisms have not been fully elucidated. Here, we report that the termination of immunotherapy strikingly increases the metastatic potential of remnant melanoma. This is mainly due to the withdrawal of IFN-, after immunotherapy. The relief of IFN-, stress led to the increase of ,v,3 integrin expression in B16 cells, which increased the adhesion of B16 cells to fibrinogen, fibronectin and laminin. Through ,v,3 signaling, the activation of FAK, upregulation of cdc2, production of active MMP-2 and MMP-9 and actin polymerization were intensified in B16 cells stimulated with ECM molecules 24 h after the withdrawal of IFN-,. The i.v. injection of such tumor cells into mice resulted in more metastatic tumor nodes in lung and shortened the survival of mice. The pitfall of immunotherapy termination can be remedied by the administration of recombinant CBD-HepII polypeptide of fibronectin, which effectively inhibits ,v,3 signaling. These findings suggest that the risk of tumor metastasis can be increased after the termination of immunotherapy, due to the withdrawal of IFN-, and that targeting ,v,3 signaling pathway can improve the therapeutic effect of immunotherapeutic approaches by reducing such metastatic risk. © 2008 Wiley-Liss, Inc. [source] Hypoxia-inducible factor-1, in non small cell lung cancer: Relation to growth factor, protease and apoptosis pathwaysINTERNATIONAL JOURNAL OF CANCER, Issue 1 2004Daniel E.B. Swinson Abstract Hypoxia-inducible factor (HIF)-1, is the regulatory subunit of HIF-1 that is stabilized under hypoxic conditions. Under different circumstances, HIF-1, may promote both tumorigenesis and apoptosis. There is conflicting data on the importance of HIF-1, as a prognostic factor. This study evaluated HIF-1, expression in 172 consecutive patients with stage I,IIIA non small cell lung cancer (NSCLC) using standard immunohistochemical techniques. The extent of HIF-1, nuclear immunostaining was determined using light microscopy and the results were analyzed using the median (5%) as a low cut-point and 60% as a high positive cut-point. Using the low cut-point, positive associations were found with epidermal growth factor receptor (EGFR; p = 0.01), matrix metalloproteinase (MMP)-9 (p = 0.003), membranous (p < 0.001) and perinuclear (p = 0.004) carbonic anhydrase (CA) IX, p53 (p = 0.008), T-stage (p = 0.042), tumor necrosis (TN; p < 0.001) and squamous histology (p < 0.001). No significant association was found with Bcl-2 or either N- or overall TMN stage or prognosis. When the high positive cut-point was used, HIF-1, was associated with a poor prognosis (p = 0.034). In conclusion, the associations with EGFR, MMP-9, p53 and CA IX suggest that these factors may either regulate or be regulated by HIF-1,. The association with TN and squamous-type histology, which is relatively more necrotic than other NSCLC types, reflects the role of hypoxia in the regulation of HIF-1,. The prognostic data may reflect a change in the behavior of HIF-1, in increasingly hypoxic environments. © 2004 Wiley-Liss, Inc. [source] Upregulation of MMP-9/TIMP-1 enzymatic system in eosinophilic meningitis caused by Angiostrongylus cantonensisINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 2 2005Ke-Min Chen Summary Proteolysis depends on the balance between the proteases and their inhibitors. Matrix metalloproteinase-9 (MMP-9) and its specific inhibitors, tissue inhibitors of metalloproteinases (TIMP), contribute to eosinophilic inflammatory reaction in the subarachnoid space of the Angiostrongylus cantonensis -infected mice. The expression of MMP-9 in cerebrospinal fluid (CSF) was significantly increased in mice with eosinophilic meningitis, compared to that in uninfected ones. However, the TIMP-1 levels were unchanged and remained at basal levels at all time points, even in uninfected mice. Elevated MMP-9 mRNA expression coincided with protein levels and proteolytic activity, as demonstrated by means of positive immunoreactivity and gelatin zymography. CSF protein contents correlated significantly with MMP-9 intensity and CSF eosinophilia. In addition, immunohistochemistry demonstrated MMP-9 and TIMP-1 localization in eosinophils and macrophages. When the specific MMP inhibitor, GM6001, was added, MMP-9 enzyme activity was reduced by 45.4%. The percentage of eosinophil increased significantly upon the establishment of infection, but subsided upon inhibition. These results show that MMP-9/TIMP-1 imbalance in angiostrongyliasis may be associated with eosinophilic meningitis. 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