Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report on the effect of prolonged hyperglycaemic (11 and 30 mM D-glucose) culture conditions on human mesangial cell matrix metalloproteinases (MMPs), plasminogen activators and their inhibitors. The results indicate that hyperglycaemic conditions modulate the potential proteolytic activity of the enzymes secreted by confluent cultures of these cells. Gelatinase A (MMP-2) activity was always higher in cultures maintained under hyperglycaemic than under normoglycaemic conditions (4 mM D-glucose). In contrast, gelatinase B (MMP-9) activity was decreased under the same conditions. Matrilysin (MMP-7) activity was decreased by up to 100% under hyperglycaemic conditions. Reverse transcriptase-PCR and Western-blotting analyses indicate that in all cases both the transcripts and the protein level were correlated with enzymic activity. One tissue inhibitor of metalloproteinases, TIMP-2, was barely detectable under hyperglycaemic conditions (30 mM D-glucose). In contrast, TIMP-1 increased during the initial 2 weeks of culture in hyperglycaemic conditions and remained elevated to the end of the experiment (4 weeks). Under normoglycaemic conditions TIMP-1 decreased after 2 weeks of culture. Hyperglycaemic conditions also decreased markedly the activity of tissue plasminogen activator (t-PA). This seemed to be due to increased synthesis of its inhibitor, plasminogen activator inhibitor 1, under these conditions rather than to decreased expression of the t-PA enzyme.
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PMID:Modulation of neutral protease expression in human mesangial cells by hyperglycaemic culture. 900 62

The serine proteinase tissue-type plasminogen activator (t-PA) and the metalloproteinase gelatinase B (MMP-9) have recently been demonstrated in MS lesions. Both enzymes are interconnected in an enzyme cascade which contributes to destruction of the blood brain barrier and demyelination and both enzymes are inhibited by D-penicillamine. Metacycline was shown in in vitro experiments to inhibit gelatinase B. The combination of peroral D-penicillamine plus metacycline was evaluated in a double-blind placebo-controlled way in two groups of 10 patients suffering from secondary progressive multiple sclerosis. The major objectives of this pilot trial were to examine the safety of this combination and the possibility of blinding, while the effect on disease progression was considered as a secondary endpoint. Over a follow-up period of 1 year and in this selected patient group, there was no significant improvement in the Expanded Disability Status Scale score (EDSS) as compared with that of the placebo-control group. Toxicity was too high to consider additional trials with this combination of metalloproteinase inhibitors. Although peroral treatment is by most MS patients acknowledged as a major improvement in treatment compliance, one has to await the development of more selective and efficacious protease inhibitors than those used in the combination therapy described here.
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PMID:Toxicity in a double-blind, placebo-controlled pilot trial with D-penicillamine and metacycline in secondary progressive multiple sclerosis. 959 37

To investigate a potential physiological role of the plasminogen/plasmin system in activation of the matrix metalloproteinase (MMP) system, the distribution of latent and active MMP-2 (gelatinase A) or MMP-9 (gelatinase B) was monitored in aorta extracts and in serum-free conditioned cell culture medium obtained from wild-type (WT) mice and from mice with deficiency of tissue-type plasminogen activator (t-PA(-/-)), urokinase-type plasminogen activator (u-PA(-/-)), plasminogen activator inhibitor-1 (PAI-1(-/-)) or plasminogen (Plg(-/-)). In aorta extracts, the contribution of active MMP-2 to the total MMP-2 level ranged between 7 and 16% for the different genotypes, whereas active MMP-9 was not detected. The contribution of active 58 kDa MMP-2 to the total MMP-2 level (active plus latent) ranged between 14 and 29% (mean of 3 experiments) for fibroblasts of the different genotypes, and between 18 and 32% for smooth muscle cells, and was relatively constant in time (7-72 h). The contribution of active 83 kDa MMP-9 to the total MMP-9 level ranged between 15 and 29% for fibroblasts of the different genotypes and was relatively constant in time (24-72 h); corresponding values were 17 to 57% for smooth muscle cells, with the exception of Plg(-/-) smooth muscle cells which had undetectable levels of active MMP-9. Addition of plasmin(ogen) to the cell culture medium of fibroblasts did not significantly affect the distribution of active and latent MMP-2, but resulted in an approximately two-fold enhancement of the contribution of active MMP-9. In macrophages of Plg(-/-) mice, active MMP-9 was detected only when the cells were cultured in the presence of plasminogen. These data indicate that activation of proMMP-2 occurs independently of the physiological plasminogen activators and of plasmin(ogen) in all the cell types evaluated. Activation of proMMP-9 was enhanced in the presence of plasmin(ogen), but active MMP-9 was also detected in fibroblasts of Plg(-/-) mice, indicating that in vivo activation may occur via plasmin(ogen)-independent mechanisms.
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PMID:Regulation of gelatinase activity in mice with targeted inactivation of components of the plasminogen/plasmin system. 965 44

Aberrant expression or activity of the epidermal growth factor (EGF) receptor family of tyrosine kinases has been associated with tumor progression and an invasive phenotype. In this study, we utilized 4 ovarian cancer cell lines, OVCA 432, DOV 13, OVEA6 and OVCA 429, to determine the effects of EGF on the regulation of proteolytic enzymes and their inhibitors, cellular migration and in vitro invasion. Induction of urinary-type plasminogen activator (u-PA) activity and tissue inhibitor of matrix metalloproteinase (TIMP)-1 was observed in all 4 cell lines. OVCA 432 cells showed strong PAI-1 induction; however, the other 3 lines displayed substantial baseline PAI-1 expression that was not induced by EGF. EGF-dependent stimulation of migration and induction of matrix metalloproteinase (MMP)-9 (gelatinase B) was observed in OVEA6 and OVCA 429 cells only. Upon EGF receptor activation, DOV 13, OVEA6 and OVCA 429 cells were induced to invade through an artificial basement membrane (Matrigel); however, no invasion was detected in OVCA 432 cells. Cell lines displaying induction of migration and MMP-9 (OVEA6 and OVCA 429) demonstrated robust EGF-induced invasion (5- to 20-fold), and cell invasion was substantially reduced in the presence of anti-catalytic MMP-9 antibody. Addition of anti-catalytic u-PA antibody inhibited the modest (<2-fold) EGF-induced invasion in a cell line that did not express MMP-9 (DOV 13) and in OVEA6 cells that displayed the highest baseline u-PA activity. Together, our findings indicate that multiple proteinases are important in ovarian cell invasion and implicate EGF induction of MMP-9 and migration as key components of more aggressive ligand-induced invasion.
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PMID:Proteinase requirements of epidermal growth factor-induced ovarian cancer cell invasion. 976 68

Normal as well as neoplastic cells traverse extracellular matrix barriers by mobilizing proteolytic enzymes in response to epidermal growth factor (EGF)-EGF receptor (EGFR) or hepatocyte growth factor/scatter factor (SF)-c-Met interactions. The plasminogen activator-plasminogen axis has been proposed to play a key role during cell invasion, but the normal development of plasminogen activator- as well as that of plasminogen-deficient mice supports the existence of alternate proteolytic systems that permit cells to traverse extracellular matrix barriers. To characterize the role that matrix-degrading proteinases play in EGF- or SF-stimulated invasion, a human squamous carcinoma cell line (UM-SCC-1) was triggered atop the matrices of type I collagen or human dermal explants in a three-dimensional culture system. During EGF- or SF-induced invasion, UM-SCC-1 cells expressed urokinase-type plasminogen activator (uPA) and uPA receptor as well as the matrix metalloproteinases (MMPs), membrane-type MMP-1, collagenase 1, stromelysin 1, and gelatinase B. Despite the presence of a positive correlation between uPA receptor-uPA expression and growth factor-stimulated invasion, UM-SCC-1 invasion was not affected by inhibitors directed against the plasminogen activator-plasminogen axis. In contrast, both recombinant and synthetic MMP inhibitors completely suppressed invasion by either EGF- or SF-stimulated cells without affecting either proteinase expression or cell motility across collagen-coated surfaces. These data demonstrate that MMPs, but not the plasminogen activator-plasmin system, can directly regulate the ability of either EGF- or SF-stimulated tumor cells to invade interstitial matrix barriers.
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PMID:Role of the plasminogen activator and matrix metalloproteinase systems in epidermal growth factor- and scatter factor-stimulated invasion of carcinoma cells. 982 36

The activation of pro matrix metalloproteinases (MMPs) by sequential proteolysis of the propeptide blocking the active site cleft is regarded as one of the key levels of regulation of these proteinases. Potential physiological mechanisms including cell-associated plasmin generation by urokinase-like plasminogen activator, or the action of cell surface MT1-MMPs appear to be involved in the initiation of cascades of pro MMP activation. Gelatinase A, collagenase 3 and gelatinase B may be activated by MT-MMP based mechanisms, as evidenced by both biochemical and cell based studies. Hence the regulation of MT-MMPs themselves becomes critical to the determination of MMP activity. This includes activation, assembly at the cell surfaces as TIMP-2 complexes and subsequent inactivation by proteolysis or TIMP inhibition.
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PMID:Mechanisms for pro matrix metalloproteinase activation. 1019 Feb 78

The role of extracellular proteolysis in inflammatory demyelination, originally hypothesized as a mechanism for myelin degradation, is increasingly recognized as a pathogenetic step and as a target for therapy in human demyelinating disease. The activation of ubiquitous plasminogen by urokinase (u-PA) and tissue-type plasminogen activator (t-PA), which is associated with various neuropathologies, including multiple sclerosis (MS), is the key initiator of the activation cascade of the four classes of matrix metalloproteinases (MMPs): collagenases, stromelysins, membrane-type metalloproteinases and gelatinases. Spatiotemporal protein and mRNA expression of gelatinase B (MMP-9) and matrilysin (MMP-7) have been documented respectively in MS lesions and in the central nervous system (CNS) of animals developing experimental autoimmune encephalomyelitis (EAE). A close interaction between disease-promoting cytokines and extracellularly acting proteases is deduced from in vitro experiments. Cytokines regulate the balance between the proteases and their respective specific inhibitors at the transcriptional level, while proteolysis is a reciprocal mechanism to enhance (by activation) or downmodulate (by degradation) the specific activities of cytokines. In acute inflammation the contribution of chemokines is hierarchically organised, interleukin-8 (IL-8) and related CXC-chemokines inducing a rapid influx of neutrophils in the acute lesions and an instantaneous exocytosis of gelatinase B granules. This results in sudden and extensive damage to the CNS. In chronic disease involving autoimmune processes CC-chemokines that act mainly on mononuclear cell types appear to be more strictly regulated. As MMPs modify matrix components, promoting extravasation of lymphocytes and monocytes/macrophages and have the potential to generate encephalitogenic peptides from myelin basic protein, novel treatments for demyelinating diseases may be predicted by specific inhibition of these enzymes. Here we review plasminogen activators and the MMP family, in the context of their role in CNS inflammation and demyelination and highlight studies in which intervention in these protease cascades are and may be used to treat demyelinating diseases.
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PMID:Plasminogen activators and matrix metalloproteases, mediators of extracellular proteolysis in inflammatory demyelination of the central nervous system. 1037 31

To investigate the role of the transcription factor nuclear factor kappaB (NFkappaB) in tumor metastasis, we generated a murine lung alveolar carcinoma cell line (Line 1) defective in NFkappaB-signaling by retroviral delivery of a dominant negative inhibitor of NFkappaB. The NFkappaB signal blockade resulted in the down-regulation of prometastatic matrix metalloproteinase 9, a urokinase-like plasminogen activator, and heparanase and reciprocal up-regulation of antimetastatic tissue inhibitors of matrix metalloproteinases 1 and 2 and plasminogen activator inhibitor 2. NFkappaB signal blockade did not affect tumor cell proliferation in vitro or in vivo but prevented intravasation of tumor cells in an in vivo chick chorioallantoic membrane model of metastasis as well as spontaneous metastasis in a murine model. These findings suggest that NFkappaB plays a central and specific role in the regulation of tumor metastasis and may be an important therapeutic target for development of antimetastatic cancer treatments.
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PMID:Tumor metastasis and the reciprocal regulation of prometastatic and antimetastatic factors by nuclear factor kappaB. 1111 32

Glycosylation influences the specific activities of serine proteases including tissue-type plasminogen activator and plasmin which act together in a ternary complex with fibrin. Serine proteases and matrix metalloproteinases (MMPs), including gelatinase B, participate in a protease cascade to remodel the extracellular matrix. In addition to the recognition and targeting functions of carbohydrates and the fact that they confer protease resistance on glycoproteins, oligosaccharides may extend particular protein domains of matrix remodelling enzymes and fine-control their activities within the context of the extracellular matrix. For example, the sialic acids of gelatinase B influence the catalytic activity of this enzyme in a complex with the tissue inhibitor of metalloproteinases-1 (TIMP-1).
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PMID:Matrix remodelling enzymes, the protease cascade and glycosylation. 1168 91

It is shown that the release of matrix metalloproteinase-9 (gelatinase B) by THP-1 and U937 cells into conditioned media is increased under the action of recombinant single-chain urokinase. This effect is not accompanied by proteolytic activation of gelatinase B and is related to release of a pro-form of the enzyme. The action of urokinase on monocytes is time-dependent and becomes significant 12-24 h after the beginning of cell incubation. The dependence of the effect on the concentration of urokinase is characterized by half-maximum at about 20 nM and saturation at about 200 nM. The urokinase-induced gelatinase B release is not dependent on the action of plasmin because plasmin inhibitors aprotinin and alpha2-antiplasmin do not abolish this action. Additionally, tissue type plasminogen activator does not induce gelatinase B release by monocytes as observed under the action of urokinase. Nevertheless, the catalytic activity of urokinase participates in the development of the observed effect because it is significantly depressed by the natural urokinase inhibitor PAI-1. The effect of urokinase is completely abolished by actinomycin D and cycloheximide, indicating the participation of transcription and translation processes in its development.
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PMID:Plasmin-independent gelatinase B (matrix metalloproteinase-9) release by monocytes under the influence of urokinase. 1170 74


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