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Results for “Matrix Metalloproteinase 9”

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At least 19 recordsLinked to original sources
PubMed1992

Matrix metalloproteinase 3 (stromelysin) activates the precursor for the human matrix metalloproteinase 9.

Matrix metalloproteinase 9 (MMP-9), also known as 92-kDa gelatinase/type IV collagenase, is secreted from neutrophils, macrophages, and a number of transformed cells in zymogen form. Here we report that matrix metalloproteinase 3 (MMP-3/stromelysin) is an activator of the precursor of matrix metalloproteinase 9 (proMMP-9). MMP-3 initially cleaves proMMP-9 at the Glu40-Met41 bond located in the middle of the propeptide to generate an 86-kDa intermediate. Cleavage of this bond triggers a change in proMMP-9 that renders the Arg87-Phe88 bond susceptible to the second cleavage by MMP-3, resulting in conversion to an 82-kDa form. alpha 2-Macroglobulin binding studies of partially activated MMP-9 demonstrate that the 82-kDa species is proteolytically active, but not the initial intermediate of 86 kDa. This stepwise activation mechanism of proMMP-9 is analogous to those of other members of the MMP family, but the action of MMP-3 on proMMP-9 is the first example of zymogen activation that can be triggered by another member of the MMP family. The results imply that MMP-3 may be an effective activator of proMMP-9 in vivo.

Amino Acid Sequence↗
PubMed2001

Systematic separation and purification of elastase, gelatinase (matrix metalloproteinase 9), and collagenase (matrix metalloproteinase 8) from polymorphonuclear leukocytes in dialyzers previously used by patients with renal failure.

We developed a simple and effective method for the systematic separation and purification of human polymorphonuclear leukocyte (PMN) proteinases, elastase, gelatinase (matrix metalloproteinase 9, type IV collagenase), and collagenase (matrix metalloproteinase 8), derived from the extracts of hollow fiber dialyzers that had been utilized in the treatment of patients with renal failure. The fraction containing elastase was grossly separated from that containing gelatinase and collagenase by heparin-Sepharose chromatography and purified in an aprotinin column. The remaining two enzymes were then separated using the gelatin-Sepharose column after gel chromatography following ammonium sulfate precipitation. Gelatinase and collagenase were further purified by gelatin-Sepharose chromatography as a latent form and by collagen-Sepharose chromatography as an activated form. This novel method offers procedural advantages over existing methods that separate PMNs from the whole blood of volunteers for experimental research purposes.

Animals↗
PubMed2005

Association study of polymorphisms within matrix metalloproteinase 9 with bronchial asthma.

Matrix metalloproteinase 9 plays an important role in the development of bronchial asthma. We were interested in whether the polymorphisms -T1702A, -C1562T, R279Q and +C6T within the matrix metalloproteinase 9 (MMP-9) gene were associated with asthma in a population of 231 asthmatic children. However, we found no association. Thus MMP-9 might not be a major gene for asthma.

Adolescent↗
PubMed2006

Extracellular matrix protein 1 inhibits the activity of matrix metalloproteinase 9 through high-affinity protein/protein interactions.

Extracellular matrix protein 1 (ECM1), an approximately 85-kDa glycoprotein with broad tissue distribution, harbors mutations in lipoid proteinosis (LP), a heritable disease characterized by reduplication of basement membranes and hyalinization of dermis, associated with neurologic disorders. The mechanisms leading from ECM1 mutations to LP phenotype are unknown. In this study, we explored ECM1 protein-protein interactions utilizing yeast two-hybrid genetic screen of human placental library, which identified nine interacting proteins, including matrix metalloproteinase 9 (MMP9). The interactions were confirmed by beta-galactosidase assay with isolated clones and by co-immunoprecipitation which narrowed the interacting segment in ECM1 to the C-terminal tandem repeat 2 (amino acids 236-361). This peptide segment also inhibited MMP9 activity in a gelatin-based ELISA assay. We propose that ECM1-mediated reduction in MMP9 proteolytic activity may have relevance to pathogenesis of LP.

Biosensing Techniques↗
PubMed2001

alpha v beta 6 Integrin upregulates matrix metalloproteinase 9 and promotes migration of normal oral keratinocytes.

The integrin alpha v beta 6 is a fibronectin receptor that is undetectable on normal keratinocytes in situ, but is increased significantly in wound healing and in culture-established keratinocytes, suggesting that it may promote changes associated with cell motility. Using normal human oral keratinocytes we have shown that cultured cells express relatively high levels of alpha v beta 6 and this integrin has a functional role in both cell adhesion and migration towards fibronectin. We provide experimental evidence that the increased expression of alpha v beta 6 by normal human oral keratinocytes results in coordinate changes, which promote a more migratory phenotype. Thus increased expression of alpha v beta 6 results in a fibronectin-dependent increase in pro-matrix metalloproteinase 9, matrix metalloproteinase 9 activity increases normal human oral keratinocyte migration, and this may be further dependent on plasmin activation. The results suggest a key role for alpha v beta 6 in these processes and indicate a coordinated link between alpha v beta 6 expression and upregulation of matrix metalloproteinase 9. It appears that alpha v beta 6 may function in normal human oral keratinocyte migration through matrix-metalloproteinase-9-dependent and -independent mechanisms.

Antigens, Neoplasm↗
PubMed2006

Expression of vascular endothelial growth factor a, matrix metalloproteinase 9 and extravascular matrix patterns in iris and ciliary body melanomas.

PURPOSE: It was the aim of this study to assess the expression of vascular endothelial growth factor (VEGF)-A, matrix metalloproteinase (MMP)-9 and extravascular matrix patterns (EMPs) in iris and ciliary body melanomas and their correlations with histopathologic parameters. METHODS: The study was conducted on 3 iris and 15 ciliary body melanomas. All tumors were subjected to immunohistochemical techniques for VEGF-A and MMP-9 expressions, the presence of EMPs was assessed, and routine paraffin sections were stained with hematoxylin-eosin. Cell type, tumor localization, degree of pigmentation, necrosis, mitotic index, lymphocytic infiltration and sclera invasion were analyzed using light microscopy. RESULTS: The mean patient age at the time of treatment was 43 years (range 19-69, median 39.5); 10 (55.6%) patients were males and 8 (44.4%) females. Histopathological cell types were spindle cells in 55.6%, mixed cells in 16.7%, and epithelioid cell types in 27.8% of tumors. Positive reaction for VEGF-A and MMP-9 was present in 66.7 and 72.3% of the tumors, respectively. Microvascular loops and/or networks were seen in 33.4% of the tumors, with the remaining 66.7% of tumors displaying one or more of the other patterns. Metastatic disease developed in only 1 patient during follow-up. Tumor cell type, tumor size, mitotic rate, degree of pigmentation and EMPs were not correlated with metastasis. CONCLUSIONS: This study suggests that VEGF-A and MMP-9 were positive in the majority of iris and ciliary body melanomas. No correlation was found between VEGF-A and MMP-9 immunoreactivity and EMPs and occurrence of metastases in cases of anterior uveal melanoma.

Adult↗
PubMed2006

C5a mediates secretion and activation of matrix metalloproteinase 9 from human eosinophils and neutrophils.

Matrix metalloproteinase 9 (MMP-9) is a crucial proteinase, utilized by both eosinophils and neutrophils, that mediates transmigration through extracellular basement membranes. We have found that neutralization of MMP-9 by a monoclonal antibody or a chemical inhibitor blocked C5a dependent chemotaxis of these granulocytes in vitro. The levels of MMP-9 secreted by the action of C5a from eosinophils were about 50-fold lower than those from neutrophils, consistent with results from confocal microscopy, where the density of MMP-9 containing granules was fewer within eosinophils than in neutrophils. Zymography indicated gelatin degrading activity of the molecular size of pro MMP-9 in supernatants from eosinophils and neutrophils stimulated by C5a, with no evidence of proteolytic activation. Instead MMP-9 activation appeared oxidative, since inhibition of NADPH oxidase and nitric oxide synthase by DPI or L-NIL abrogated C5a-mediated chemotaxis through basement membranes. In keeping with this mode of activation, C5a, known as an agent of superoxide generation, was also found to induce secretion of nitric oxide from human eosinophils and rat granulocytes and monocytes. In conclusion C5a is an important mediator that brings about secretion and oxidative activation of MMP-9, a requisite protease for transmigration, from both eosinophils and neutrophils.

Animals↗
PubMed1998

alpha2beta1 integrin signaling via the mitogen activated protein kinase pathway modulates retinoic acid-dependent tumor cell invasion and transcriptional downregulation of matrix metalloproteinase 9 activity.

Tumor cell invasion and metastasis requires precise coordination of adherence to the extracellular matrix (ECM) and controlled degradation of its components. lnvasive cells secrete proteolytic enzymes known as matrix metalloproteinases which degrade specific basement membrane molecules. Expression of these enzymes is regulated by multiple signaling mechanisms, including attachment to the extracellular matrix via integrins. All-trans retinoic acid can inhibit tumor cell invasion of ECM by regulating matrix metalloproteinase expression. Using a series of squamous cell carcinoma lines, we investigated the interactions between integrin and retinoic acid signaling in these cells. In a cell line sensitive to RA-mediated inhibition of invasion, this ligand downregulated MMP-9 activity in cells grown on specific ECM molecules but not on plastic. Inhibition of integrin signaling with anti-alpha1 antibodies or MAPK pathway inhibitors abrogated RA mediated down-regulation of MMP-9 activity and invasion. The effects of RA and MAPK signaling on MMP-9 activity was mediated at the transcriptional level. These data indicate that crosstalk between RA- and integrin dependent signaling pathways regulate MMP activity and invasion in squamous cell carcinoma lines.

Antineoplastic Agents↗
PubMed2001

Coronary artery complicated lesion area is related to functional polymorphism of matrix metalloproteinase 9 gene: an autopsy study.

Matrix metalloproteinase 9 (MMP9) is expressed in human atherosclerotic plaques, and the protein is localized in human coronary atherosclerotic lesions. The MMP9 gene has a C-to-T promoter polymorphism at position -1562, which affects transcription and leads to promoter low-activity (C/C) and high-activity (C/T, T/T) genotypes. To determine whether these genotypes exert an influence on the atherosclerotic lesion area, we investigated their association with different types of coronary lesions in an autopsy cohort of 276 men aged 33 to 69 years. Areas of the coronary wall covered with fatty streaks and fibrotic, calcified, and complicated lesions were measured, and the percentage of coronary narrowing was determined. MMP9 genotypes were determined by polymerase chain reaction and restriction enzyme digestion. In men aged >/=53 years, the mean area of complicated lesions in 3 coronaries was significantly associated with the MMP9 genotype (P=0.008). Subjects with high promoter activity genotypes had, on average, larger complicated lesion areas than did those with the low-activity genotype. The MMP9 genotype persisted as an independent predictor of complicated lesion area after adjustment for age, body mass index, hypertension, diabetes, and smoking (P=0.012). These data provide evidence that the proposed effect of MMP9 in the process of atherosclerotic lesion development may be modified by the MMP9 genotype.

Adult↗
PubMed2006

Prestorage leukoreduction prevents accumulation of matrix metalloproteinase 9 in stored blood.

OBJECTIVES: Transfusion of aged stored blood is associated with many neutrophil proinflammatory effects. The mechanism of these effects remains to be elucidated. The purpose of this study was to determine whether matrix metalloproteinases accumulate in packed red blood cells during storage and are responsible for some of the neutrophil proinflammatory events, and to determine whether prestorage leukoreduction prevents accumulation of matrix metalloproteinases and attenuates proinflammatory effects of stored packed red blood cells. DESIGN: Laboratory study. PARTICIPANTS: Healthy human volunteers. INTERVENTIONS: Units of blood were drawn from healthy volunteers. Half of each unit was filtered for leukoreduction, removing 99.9% of leukocytes. At biweekly intervals, aliquots were removed from packed red blood cell units, and the plasma fraction was isolated for assays. Plasma was assayed for specific molecules or incubated with isolated neutrophils, with or without a matrix metalloproteinase 9 inhibitor. MAIN OUTCOME MEASURES: Concentrations of matrix metalloproteinases 2 and 9 and tissue inhibitor of metalloproteinase 1; matrix metalloproteinase 9 activity; and neutrophil apoptosis. RESULTS: Concentrations of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 but not matrix metalloproteinase 2 increased over time. This accumulation was abolished by leukoreduction. Matrix metalloproteinase 9 accumulated in an active form. Both leukoreduction and matrix metalloproteinase 9 inhibition reversed stored packed red blood cell-induced, delayed neutrophil apoptosis. CONCLUSIONS: Storage of packed red blood cells for 14 days or more is associated with increases in the concentrations of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1, with the enzyme in excess of its inhibitor. Prestorage leukoreduction prevents this accumulation. Delayed neutrophil apoptosis related to packed red blood cell plasma appears to be due, in part, to matrix metalloproteinase 9. Leukoreduction can help prevent the effects of matrix metalloproteinase 9 on neutrophil apoptosis.

Analysis of Variance↗
PubMed1999

Human mast cells produce matrix metalloproteinase 9.

Extracellular matrix-destructive enzymes, like matrix metalloproteinases (MMP), have been recognized in the process of inflammation and tissue remodeling and repair. The affected tissues often contain markedly increased numbers of mast cells. Although mast cells are capable of activating latent collagenase and proMMP, it has so far been unknown whether human mast cells themselves produce and secrete MMP9. In this study, MMP9 production by cord blood-derived cultured human mast cells and HMC-1 human mast cells was examined by reverse-transcriptase PCR, gelatin zymography and Western blot analysis using an antibody against MMP9. Cultured mast cells and HMC-1 cells treated with phorbol 12-myristate 13-acetate were shown to express MMP9 mRNA, and the cultured conditioned media from these cells showed gelatinolytic activity, identical with MMP9. Immunohistochemical examination was performed to detect MMP9 in tissue mast cells; mast cells localized in the skin, lung and synovial tissue showed strongly positive reactions for MMP9. Thus, these findings indicate that human mast cells can produce MMP9, which might contribute to extracellular matrix degradation and absorption in the process of allergic and nonallergic responses.

Base Sequence↗
PubMed2001

Blood specimen collection methods influence the concentration and the diagnostic validity of matrix metalloproteinase 9 in blood.

BACKGROUND: Matrix metalloproteinases (MMP) in blood are promising new diagnostic tools. It was shown that the blood sampling process resulted in different blood concentrations of MMPs. To clarify whether the sampling process also influences the diagnostic validity of MMPs, MMP-9 measurements were performed in plasma and serum samples of patients with prostate carcinoma and renal cell cancer. METHODS: MMP-9 ELISAs were performed in samples of heparin plasma and serum collected in blood tubes with and without clot accelerator. Measurements were undertaken in 78 healthy persons, 33 patients with prostate carcinoma and 33 patients with renal cell carcinoma. RESULTS: MMP-9 showed higher concentrations in serum samples than in heparin plasma and was about threefold higher in serum samples collected in tubes with clot activator than in native serum samples. Both patient groups had lower MMP-9 concentrations in serum, whereas in plasma, patients with renal cell carcinoma had higher, but patients with prostate cancer unchanged MMP-9 concentrations. 13 of 33 patients with renal cell carcinoma had increased MMP-9 plasma values but no patient had increased serum concentrations. CONCLUSIONS: To optimise the diagnostic validity of the MMP-9 in blood, measurements should be performed in heparin plasma but not in serum.

Blood Specimen Collection↗
PubMed2000

Relationship between cell-associated matrix metalloproteinase 9 and psoriatic keratinocyte growth.

Primary cultures of psoriatic keratinocytes proliferated at a higher rate and produced lower amounts of matrix metalloproteinase 9 than normal keratinocytes cultured under similar conditions. Sup- plementation of psoriatic keratinocyte cell culture medium with batimastat or the use of a matrix metalloproteinase 9 blocking antibody further stimulated psoriatic keratinocyte growth. An increase in intracellular ceramide level enhanced matrix metalloproteinase 9 production and inhibited cell proliferation in parallel. Whether cells were treated with sphingomyelinase or not, however, conditioned media from psoriatic keratinocytes contained higher levels of tissue inhibitor of metalloproteinase-1 compared with matrix metalloproteinase 9 and secreted only the proenzyme form. Pro-matrix metalloproteinase 9, as well as active matrix metalloproteinase 9, was identified in membrane preparations of psoriatic keratinocytes, and enzyme amounts were greatly elevated following sphingomyelinase action. As (i) tissue inhibitor of metalloproteinase-1 antibody nearly totally abrogated keratinocyte growth and (ii) complexes of tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase 9 were recovered in membrane extracts of sphingomyelinase-treated psoriatic keratinocytes, we postulate that an increased level of cell-associated matrix metalloproteinase 9 might compete for tissue inhibitor of metalloproteinase-1 binding to its receptor. As a consequence, the increased levels of matrix metalloproteinase 9 will decrease keratinocyte growth.

Adult↗
PubMed2006

Urinary levels of matrix metalloproteinase 9 and 2 and tissue inhibitor of matrix metalloproteinase in patients with coronary artery disease.

OBJECTIVES: To evaluate the feasibility of an assay for urinary levels of matrix metalloproteinases (MMPs) and the potential usefulness of urinary MMPs as a marker of coronary atherosclerosis or acute coronary syndromes (ACS). METHODS AND RESULTS: We measured urine and plasma MMP-9, MMP-2 and urine tissue inhibitor of metalloproteinase (TIMP-1) in patients with ACS (n=27), patients with coronary artery disease (CAD), but no clinical instability (n=47) and a group of healthy volunteers (n=15) who were <35 years of age, had no risk factors for CAD and did not undergo angiography. Compared with volunteers, patients with ACS and CAD had higher urine MMP-9, urine TIMP-1, plasma MMP-9 and plasma MMP-2 levels, but these did not differ between those with CAD and ACS. Using the volunteers to roughly establish an upper limit of normal, 84% of the urine TIMP-1 values and 95% of the urine MMP-9 values were abnormally elevated among those with CAD and ACS. CONCLUSIONS: Urine MMP-9 and TIMP-1 levels are elevated in patients with CAD and ACS compared with healthy volunteers. A high percent of patients with CAD or ACS had elevated urine values of MMP-9 and TIMP-1 suggesting these variables might be a useful marker of atherosclerotic disease.

Acute Disease↗
PubMed2001

Statins suppress THP-1 cell migration and secretion of matrix metalloproteinase 9 by inhibiting geranylgeranylation.

Macrophages secrete matrix metalloproteinase 9 (MMP-9), an enzyme that weakens the fibrous cap of atherosclerotic plaques, predisposing them to plaque rupture and subsequent ischemic events. Recent work indicates that statins strongly reduce the possibility of heart attack. Furthermore, these compounds appear to exert beneficial effects not only by lowering plasma low-density-lipoprotein cholesterol but also by directly affecting the artery wall. To evaluate whether statins influence the proinflammatory responses of monocytic cells, we studied their effects on the chemotactic migration and MMP-9 secretion of human monocytic cell line THP-1. Simvastatin dose dependently inhibited THP-1 cell migration mediated by monocyte chemoattractant protein 1, with a 50% inhibitory concentration of about 50 nM. It also inhibited bacterial lipopolysaccharide-stimulated secretion of MMP-9. The effects of simvastatin were completely reversed by mevalonate and its derivatives, farnesylpyrophosphate and geranylgeranyl pyrophosphate, but not by ubiquinone. Additional studies revealed similar but more profound inhibitory effects with L-839,867, a specific inhibitor of geranylgeranyl transferase. However, alpha-hydroxyfarnesyl phosphonic acid, an inhibitor of farnesyl transferase, had no effect. C3 exoenzyme, a specific inhibitor of the prenylated small signaling Rho proteins, mimicked the inhibitory effects of simvastatin and L-839,867. These data supported the role of geranylgeranylation in the migration and MMP-9 secretion of monocytes.

ADP Ribose Transferases↗
PubMed2006

Captopril, an Angiotensin-converting enzyme inhibitor, attenuates the severity of acute pancreatitis in rats by reducing expression of matrix metalloproteinase 9.

It has been reported that matrix metalloproteinase 9 (MMP-9) disrupts basement membrane and increases vascular permeability. MMP-9 therefore might participate in the pathogenesis of severe acute pancreatitis (SAP). Captopril, an angiotensin-converting enzyme inhibitor, could reduce MMP-9 expression. However, the effect of captopril on the outcome of SAP is not ascertained. The aim of this study was to determine whether captopril attenuates the severity of SAP by reducing MMP-9 expression. Thirty Sprague-Dawley rats were randomly divided into 3 groups (n = 10 for each). Rats were given intraperitoneal injection of saline (SAP group) or captopril (4 mg/kg) (treated group), and then given retrograde infusion of 5% sodium taurocholate (1.5 ml/kg) into the pancreatic duct under laparotomy to induce SAP. One group of rats, injected with saline, underwent only sham operation (Control). Experimental samples were collected at 24 hrs after the induction of SAP or sham operation. Various markers of severity of SAP, such as serum levels of amylase and trypsinogen activation peptide and the vascular permeability, were increased in rats with SAP, but were significantly decreased in captopril-treated rats (p < 0.01). Likewise, the serum MMP-9 levels and expression levels of pancreatic tissue MMP-9 were significantly higher in rats with SAP than those in captopril-treated rats and control rats (p < 0.01 for both parameters), but showed no difference between captopril-treated and control rats. These results suggest that captopril may attenuate vascular permeability by reducing MMP-9 expression in SAP, thereby ameliorating severity of the disease. The use of captopril might become a new therapeutic agent for SAP.

Amylases↗
PubMed1995

Preferential inactivation of tissue inhibitor of metalloproteinases-1 that is bound to the precursor of matrix metalloproteinase 9 (progelatinase B) by human neutrophil elastase.

The precursor of matrix metalloproteinase 9 (pro-MMP-9) forms a complex with the tissue inhibitor of metalloproteinases (TIMP)-1 through the C-terminal domain of each molecule, and the N-terminal domain of TIMP-1 in the complex interacts and inhibits active MMPs. We have reported that a catalytic amount of MMP-3 (stromelysin 1) activates pro-MMP-9 (Ogata, Y., Enghild, J. J., and Nagase, H. (1992) J. Biol. Chem. 267, 3581-3584). To activate pro-MMP-9 in the complex, however, an excess molar amount of MMP-3 is required to saturate the TIMP-1 in the complex. The aim of this study was to test the hypothesis that the requirement for excess MMP-3 can be circumvented by specific destruction of TIMP-1 by non-target proteinases. We have tested trypsin, plasmin, cathepsin G, neutrophil elastase, and chymotrypsin as possible inactivators of TIMP-1 and found that neutrophil elastase inactivates TIMP-1 in the complex without significant destruction of pro-MMP-9. Once TIMP-1 is inactivated, pro-MMP-9 can be readily activated by a catalytic amount of MMP-3. These results suggest that neutrophil elastase may participate in the connective tissue destruction at the inflammatory sites not only by its direct action on matrix macromolecules but also by rendering pro-MMP-9 in the pro-MMP-9.TIMP-1 complex activable by MMP-3 as well as activating pro-MMP-3.

Cells, Cultured↗