Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.17 (MMP-3)
3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinases (MMPs) are a major group of enzymes that regulate cell-matrix composition. MMP genes show a highly conserved modular structure. Ample evidence exists on the role of MMPs in normal and pathological processes, including embryogenesis, wound healing, inflammation, arthritis, cardiovascular diseases, pulmonary diseases and cancer. The expression patterns of MMPs have interesting implications for the use of MMP inhibitors as therapeutic agents. Insights might be gained as to the preference for a general MMP inhibitor as opposed to an inhibitor designed to be specific for certain MMP family members as it relates to a defined disease state, and may give clues to potential side effects. The signalling pathways that lead to induction of expression of MMPs are still incompletely understood, but certain patterns are beginning to emerge. Regarding inhibition of MMP expression at the level of kinase pathways, it is possible that selective chemical inhibitors for distinct signalling pathways (e.g. MAPK, PKC) will hopefully, soon be available for initial clinical trials. Overexpression of selective dual specificity MAPK phosphatases have been shown to prevent MMP promoter activation which could also be used as a novel strategy to prevent activation of AP-1 and ETS transcription factors and MMP promoters in vivo. Interactions between members of different transcription factors provide fine-tuning of the transcriptional regulation of MMP promoter activity. MMPs play a crucial role in tumor invasion. Although the expression of MMPs in malignancies has been studied widely, the specific role of distinct MMPs in the progression of cancer may be more complex than has been assumed. For example, it has recently been shown that MMP-3, MMP-7, MMP-9 and MMP-12 can generate angiostatin from plasminogen, indicating that their expression in peritumoral area may in fact serve to limit angiogenesis and thereby inhibit tumor growth and invasion. The recent view about the role of stromal cells in the progression of cancer cell growth and metastasis is particularly interesting, and additional studies about the regulation of MMP gene expression and activity in malignancies are needed to understand the role and regulation of MMPs in tumor cell invasion.
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PMID:Regulation of matrix metalloproteinases: an overview. 1461 79

C18 unsaturated fatty acids were here found to inhibit proMMP (matrix metalloproteinase)-3 activation by plasmin. This effect was suppressed by lysine ligand competitors, indicating that it was mediated by binding to kringle domains. Surface plasmon resonance analysis demonstrated that oleic acid interacted to a similar extent with plasmin and kringle 5 (KD values of 3.4 x 10(-8) and 5.9 x 10(-8)M) while interaction with kringles 1-2-3 was 10-fold lower. Furthermore, oleic acid stimulated the amidolytic activity of plasmin and mini-plasmin, but not micro-plasmin. Oleic acid also enhanced u-PA (urokinase-type plasminogen activator)-mediated plasminogen activation over 50-fold. Taken together, these data indicate that inhibition of plasmin-induced proMMP-3 activation by unsaturated fatty acids was mediated through their preferential binding to kringle 5. The influence of elaidic acid on the plasmin/MMP-3/MMP-1 proteolytic cascade was assessed ex vivo. Exogenous addition of plasmin to dermal fibroblasts or supplementation of gingival fibroblast culture medium with plasminogen triggered this cascade. In both instances, elaidic acid totally abolished proMMP-3 and proMMP-1 activation. Additionally, a significant decrease in lattice retraction and collagen degradation in a range similar to that obtained with Batimastat was observed when human gingival fibroblasts were cultured in plasminogen-containing type I collagen gels, indicative of the dual influence of unsaturated fatty acids on MMP activation and activity. In conclusion, unsaturated fatty acids or molecules with similar structures could be attractive target for the development of natural pharmacological inhibitors directed against plasmin and/or MMPs in different pathological contexts such, skin UV irradiation, vascular diseases and tumour growth and invasion.
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PMID:Inhibition of plasmin-mediated prostromelysin-1 activation by interaction of long chain unsaturated fatty acids with kringle 5. 1475 64

As cancer cells traverse collagen-rich extracellular matrix (ECM) barriers and intravasate, they adopt a fibroblast-like phenotype and engage undefined proteolytic cascades that mediate invasive activity. Herein, we find that fibroblasts and cancer cells express an indistinguishable pericellular collagenolytic activity that allows them to traverse the ECM. Using fibroblasts isolated from gene-targeted mice, a matrix metalloproteinase (MMP)-dependent activity is identified that drives invasion independently of plasminogen, the gelatinase A/TIMP-2 axis, gelatinase B, collagenase-3, collagenase-2, or stromelysin-1. In contrast, deleting or suppressing expression of the membrane-tethered MMP, MT1-MMP, in fibroblasts or tumor cells results in a loss of collagenolytic and invasive activity in vitro or in vivo. Thus, MT1-MMP serves as the major cell-associated proteinase necessary to confer normal or neoplastic cells with invasive activity.
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PMID:Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP. 1555 25

The deposition of the insoluble protein matrix, fibrin is temporary. The mainly known mechanism of proteolytic removal is orchestrated by a cascade type of proteolytic process involving ultimately the formation from plasminogen of the active degradation enzyme plasmin. The occurrence of plasminogen deficiency without a massive deposition of fibrin and thrombotic events indicates the occurrence of alternate routes of fibrin degradation. In the literature, data have been reported about the direct fibrinolytic activity of various other enzymes including leucocytal elastase and cathepsin G and three metalloproteinases (MMP-3,MMP-7, MT1-MMP). The importance of each of these pathways and the possible differences in importance in various diseases, in acute situations and at different locations in the circulation, in tissues and organs is not known in detail. It is suggested that multiple combined knock-outs be created to evaluate the situation for various well-defined phenotypes. It is concluded that fibrin removal is an important biological process with various buffering mechanisms and only combinations of abnormalities in the various mechanisms and special situations will lead to fibrin accumulation and thrombotic events.
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PMID:The fibrinolytic system and thrombotic tendency. 1569 55

Extracellular proteolysis by the plasminogen/plasmin (Plg/plasmin) system and MMPs is required for tissue injury in autoimmune and inflammatory diseases. We demonstrate that a Plg cascade synergizes with MMP-9/gelatinase B in vivo during dermal-epidermal separation in an experimental model of bullous pemphigoid (BP), an autoimmune disease. BP was induced in mice by antibodies to the hemidesmosomal antigen BP180. Mice deficient in MMP-9 were resistant to experimental BP, while mice deficient in Plg and both tissue Plg activator (tPA) and urokinase Plg activator (uPA) showed delayed and less intense blister formation induced by antibodies to BP180. Plg-deficient mice reconstituted locally with Plg or the active form of MMP-9 (actMMP-9), but not the proenzyme form of MMP-9 (proMMP-9), developed BP. In contrast, proMMP-9 or actMMP-9, but not Plg, reconstituted susceptibility of MMP-9-deficient mice to the skin disease. In addition, MMP-3-deficient mice injected with pathogenic IgG developed the same degree of BP and expressed levels of actMMP-9 in the skin similar to those of WT controls. Thus, the Plg/plasmin system is epistatic to MMP-9 activation and subsequent dermal-epidermal separation in BP.
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PMID:Synergy between a plasminogen cascade and MMP-9 in autoimmune disease. 1584 Nov 69

Liver fibrosis and cirrhosis involve multiple cellular and molecular events that lead to deposition of an excess of extracellular matrix proteins and increase the distortion of normal liver architecture. Etiologies include chronic viral hepatitis, alcohol abuse and drug toxicity. Degradation of these matrix proteins occurs predominantly as a result of a family of enzymes called metalloproteases (MMPs) that specifically degrade collagenous and non-collagenous substrates. Matrix degradation in the liver is due to the action of at least four of these enzymes: MMP-1, MMP-2, MMP-3 and MMP-9. In the fibrinolytic system, MMPs can be activated through proteolytic cleavage by the action of urokinase plasminogen activator; a second mechanism includes the same metalloproteases. This activity is regulated at many levels in the fibrinolytic system. The main regulator is the PAI-1. This molecule blocks the conversion of plasminogen into plasmin, and the MMP cannot be activated. At a second level, the inhibition is possible by binding to inhibitors called TIMP that can inhibit the proteolitic activity even when the MMPs had been previously activated by plasmin. During abnormal conditions, overexpression of these inhibitors is directed by the transforming growth factor-beta that in a fibrotic disease acts as an extremely important adverse factor.
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PMID:[Hepatic fibrosis: role of matrix metalloproteases and TGFbeta]. 1616 29

Bone matrix turnover is regulated by matrix metalloproteinases (MMPs), tissue inhibitors of matrix metalloproteinases (TIMPs), and the plasminogen activation system, including tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), and plasminogen activator inhibitor type-1 (PAI-1). We previously demonstrated that 1.0g/cm(2) of compressive force was an optimal condition for inducing bone formation by osteoblastic Saos-2 cells. Here, we examined the effect of mechanical stress on the expression of MMPs, TIMPs, tPA, uPA, and PAI-1 in Saos-2 cells. The cells were cultured in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum and with or without continuously compressive force (0.5-3.0g/cm(2)) for up to 24h. The levels of MMPs, TIMPs, uPA, tPA, and PAI-1 gene expression were estimated by determining the mRNA levels using real-time PCR, and the protein levels were determined using ELISA. The expression levels of MMP-1, MMP-2, MMP-14, and TIMP-1 markedly exceeded the control levels at 1.0g/cm(2) of compressive force, whereas the expression levels of MMP-3, MMP-13, TIMP-2, TIMP-3, TIMP-4, tPA, uPA, and PAI-1 markedly exceeded the control levels at 3.0g/cm(2). These results suggest that mechanical stress stimulates bone matrix turnover by increasing these proteinases and inhibitors, and that the mechanism for the proteolytic degradation of bone matrix proteins differs with the strength of the mechanical stress.
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PMID:Effect of compressive force on the expression of MMPs, PAs, and their inhibitors in osteoblastic Saos-2 cells. 1651 40

Elastin peptides were previously reported to increase MMP expression in several cell types. We found binding of these peptides to their receptors led to enhanced MMP-3 and MMP-1 expression, but not activation, in human gingival fibroblasts cultured on plastic dishes. We hypothesized that these peptides, in a more physiological environment, might additionally trigger an MMP-3/MMP-1 activation cascade, leading to matrix lysis, as occurs in periodontitis. To test this hypothesis, we used contracted and attached lattices as gingival lamina propria equivalents. In such 3D models, supplementation of elastin peptides and plasminogen triggered an MMP-3/MMP-1 activation cascade and significant down-regulation of TIMPs production, further leading to intense collagen degradation. We propose that elastolysis, as occurs in periodontitis, potentiates collagenolysis, thus promoting disease progression.
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PMID:Elastolysis induces collagenolysis in a gingival lamina propria model. 1686 Dec 93

The aim of the study was to investigate the effect of functional polymorphisms in promoters of the MMP-2 (-1306 C > T), MMP-3 (-1171 5A > 6A), MMP-9 (-1562 C > T), MMP-12 (-82 A > G), TIMP-1 (-372 C > T), and PAI-1 (-675 4G > 5G and -847 A > G) genes on the growth rate of small abdominal aortic aneurysms. The patients with small aneurysms were recruited from the surveillance arm of the U.K. Small Aneurysm Trial and monitored for aneurysm growth, mean follow-up 2.6 years. Mean linear aneurysm growth rates were calculated by flexible modeling. For MMP-2, MMP-3, MMP-9, MMP-12, and TIMP-1 polymorphisms there were no clear associations with aneurysm growth. The increased growth rates for patients of 5G5G PAI-1 genotype were of borderline significance (P = 0.06). However, PAI-1 haplotype analysis showed that 5G5G/GG patients had significantly faster aneurysm growth (mean 0.46 mm/year faster). There was no evidence that any specific MMP polymorphism had a clinically significant effect on aneurysm growth. However the plasminogen system (via PAI-1) appears to have a small, but clinically significant, role in aneurysm growth.
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PMID:Genes predisposing to rapid aneurysm growth. 1718 40

Fibroblasts, a major constituent of gingival connective tissue, can produce immunoregulatory cytokines and proteolytic enzymes that may contribute to tissue destruction. In this study, we evaluated the production of matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs), and plasminogen activators by gingival fibroblasts stimulated with lipopolysaccharides (LPS) produced by periodontopathogens, including Actinobacillus actinomycetemcomitans. In addition, changes in the expression and phosphorylation state of fibroblast intracellular signaling proteins induced by A. actinomycetemcomitans LPS were characterized using antibody microarrays. We showed that A. actinomycetemcomitans LPS induced the production of a 50 kDa plasminogen activator, MMP-2 and, to a lesser extent, MMP-3 by fibroblasts. The stimulation of fibroblasts with A. actinomycetemcomitans LPS also resulted in the overproduction of TIMP-1, but had no effect on the production of TIMP-2. Comparable responses were also obtained with Porphyromonas gingivalis and Fusobacterium nucleatum subsp. nucleatum LPS. The results of the microarray analyses showed that A. actinomycetemcomitans LPS induced changes in the phosphorylation state and expression of gingival fibroblast intracellular signaling proteins. More specifically, they suggested that A. actinomycetemcomitans LPS may induce both Jun N-terminus protein-serine kinases (JNK) and mitogen-activated protein-serine kinase p38 alpha (p38alpha MAPK) pathway activation, leading to increased activator protein-1 (AP-1) and nuclear factor kappa-B (NFkappaB) activities, which in turn can stimulate MMP-2, MMP-3, TIMP-1, and urokinase-type plasminogen activator (uPA) expression. This may contribute to periodontal connective tissue destruction.
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PMID:Actinobacillus actinomycetemcomitans lipopolysaccharide regulates matrix metalloproteinase, tissue inhibitors of matrix metalloproteinase, and plasminogen activator production by human gingival fibroblasts: a potential role in connective tissue destruction. 1729 2


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