EC:3.4.24.17 - FACTA Search

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

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

Matrix metalloproteases (MMP) constitute a family of proteolytic enzymes degrading extracellular matrix components. Their activity is inhibited by tissue inhibitors of metalloproteases (TIMP). Previous studies have demonstrated that various cytokines can modulate MMP and TIMP gene expression. In this study, we demonstrate that interferon-gamma coordinately upregulates MMP-1 (interstitial collagenase) and MMP-3 (stromelysin-1) gene expression in cultured keratinocytes, as determined at the mRNA steady-state levels, and this effect is dependent on on-going protein synthesis. In contrast, there was no effect on TIMP-1 gene expression. Enhanced MMP-1 expression by IFN-gamma was also demonstrated at the protein level by Western analysis. Transient transfections with MMP-1 and MMP-3 promoter/reporter gene constructs revealed no response to IFN-gamma, whereas incubation of keratinocytes with this cytokine appeared to stabilize the MMP-1 mRNA, resulting in reduced turnover of the transcript. These data suggest that IFN-gamma enhances MMP gene expression at the post-transcriptional level. The altered MMP expression by IFN-gamma without concomitant effect on TIMP gene expression potentially leads to imbalance between these proteases and their inhibitors, and enhanced proteolytic activity may play a role in the remodeling of cutaneous tissue involving inflammatory processes, such as wound healing.
...
PMID:Interferon-gamma coordinately upregulates matrix metalloprotease (MMP)-1 and MMP-3, but not tissue inhibitor of metalloproteases (TIMP), expression in cultured keratinocytes. 786 Oct 7

Connective tissue remodeling is essential for normal growth and development, and many diseases have long been associated with the breakdown of the collagenous matrix of bone, cartilage, and related tissues. Recent work has established that members of the family of matrix metalloproteinases (MMPs) are key enzymes in matrix degradation. They function at neutral pH and can digest synergistically all the matrix macromolecules. Biochemical and cloning studies indicate that there are three major groups, collagenases, gelatinases, and stromelysins. Naturally occurring inhibitors, TIMPs (Tissue Inhibitors of MetalloProteinases), are important controlling factors in the actions of MMPs, and tissue destruction in disease processes often correlates with an imbalance of MMPs over TIMPs. The major inhibitor is TIMP-1 (or TIMP), a 30-kDa glycoprotein that is synthesized by most cells. The expression of MMPs and TIMPs by cells is regulated by many cytokines (particularly interleukin-1, IL-1), growth factors, and hormones, some of which are specific to cell type and others that are ubiquitous (e.g., transforming growth factor beta, TGF-beta). One way in which pathogenic organisms might mediate tissue degradation in periodontal diseases is through the ability of cell wall antigens to stimulate cytokine production by circulating mononuclear cells. These would then induce MMP synthesis by resident gingival cells, thereby initiating degradative events. Direct in vivo evidence for the source of collagenase and other MMPs in periodontal tissues is limited. By using specific polyclonal antibodies and indirect immunofluorescence, we could demonstrate the presence of collagenase, stromelysin-1, gelatinase A, and TIMP in human gingival biopsy specimens.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Connective tissue degradation in health and periodontal disease and the roles of matrix metalloproteinases and their natural inhibitors. 786 92

Hepatic fibrosis occurs as a consequence of net accumulation of matrix proteins (particularly collagen types I and III) in liver. Current concepts of the pathogenesis of liver fibrosis place major emphasis on the activation of hepatic lipocytes (fat-storing or Ito cells) to a myofibroblast-like phenotype with a consequent increase in their synthesis of matrix proteins. While this is an important factor, there is increasing evidence to indicate that liver fibrosis is a dynamic pathologic process in which altered matrix degradation may also play a significant role. Extracellular degradation of matrix proteins is regulated by a family of enzymes called the matrix metalloproteinases, which is subdivided into three groups; collagenases which degrade interstitial collagens (types I, II and III), type IV collagenases/gelatinases which degrade basement membrane (type IV) collagen and gelatins and stromelysins which degrade a broad range of substrates including proteoglycans, laminin, gelatins and fibronectin. The extracellular activity of these enzymes is regulated by several mechanisms which include alterations in gene transcription and proenzyme synthesis, cleavage of secreted proenzymes to active forms, and specific inhibition of activated forms by tissue inhibitor(s) of metalloproteinases (TIMPs). In liver, current evidence indicates that activated hepatic lipocytes and Kupffer cells play a central role in synthesis of matrix metalloproteinases. Under defined conditions they synthesize interstitial collagenase, 72 kDa and 95 kDa type IV collagenase/gelatinase and possibly stromelysin. Moreover, lipocytes also contribute to regulation of the extracellular activity of these enzymes by secretion of TIMP-1 and alpha 2-macroglobulin.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Degradation of matrix proteins in liver fibrosis. 789 31

The present study was designed to assess whether expression of mRNA for extracellular matrix (ECM) components, metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) in glomeruli is affected by a low protein diet during the course of focal glomerulosclerosis (FGS). Puromycin aminonucleoside (PAN) was injected intraperitoneally in rats and the right kidney was removed on day 22. Nephrotic rats received successive intraperitoneal injections of PAN on days 27, 34, and 41. Control rats were subjected to a nephrectomy or a sham operation on day 22. Animals were divided into six groups. In group 1, the PAN-injected rats were fed a standard diet containing 22% protein. In group 2, the PAN-injected rats were fed a low protein diet containing 6% protein, starting on the same day as the first PAN injection. In group 3, the nephrectomized rats without PAN were fed a standard diet. In group 4, the nephrectomized rats without PAN were fed a low protein diet for the same period. In group 5, the sham operated rats were fed a standard diet. In group 6, the sham operated rats were fed a low protein diet for the same period. Rats were sacrificed on days 0, 60 or 80 after the initial PAN or saline injection. The percentage of sclerotic glomeruli in group 1 rats increased markedly with time, reaching 77% on day 80. The mRNA levels encoding for alpha 1(I), alpha 1(III), alpha 1(IV) collagen chains, laminin B1 and B2 chains, heparan sulfate proteoglycan (HSPG), MMP-2, TIMP-1 and TIMP-2 increased significantly as glomerulosclerosis progressed, whereas MMP-1 and MMP-3 mRNA levels were unchanged, and no MMP-9 mRNA was detected throughout the experiments. In group 2, the low protein diet reduced the prevalence of glomerulosclerosis and attenuated the increased mRNA expression for ECM components, MMP-2, TIMP-1 and TIMP-2 in FGS glomeruli. In groups 3 through 6, mRNA levels for ECM components decreased with age, whereas those for MMPs and TIMPs changed little throughout the experiments. Immunofluorescence studies revealed the accumulation of types I, III and IV collagens, laminin, and HSPG in the sclerotic area and low protein diet attenuated the accumulation of these proteins. These data suggest that glomerulosclerosis may result from an imbalance among ECM components, MMPs and TIMPs and that a low protein diet attenuates the otherwise increased levels of mRNA for ECM components, MMP-2, TIMP-1 and TIMP-2 in glomerulosclerosis.
...
PMID:Low protein diet blunts the rise in glomerular gene expression in focal glomerulosclerosis. 793 7

The tissue inhibitors of metalloproteinases (TIMPs) are proteins that specifically inhibit the matrix metalloproteinases. They consist of two distinct structural and functional domains. In order to elucidate the role of these domains, we have prepared mutants of TIMP-1 and TIMP-2 that lack a C-terminal domain. The N-terminal domain alone is an efficient inhibitor of all the matrix metalloproteinases through interaction with the enzyme catalytic domain. The C-terminal domain has at least two separate enzyme binding sites, one for gelatinase A and the other for stromelysin-1. The rate of inhibition of either enzyme is increased by interaction with the TIMP C-terminal domain. As no conformational change is observed, we propose that the rate enhancement is due to an anchoring effect in which binding of the TIMP C-terminal domain aligns the TIMP N-terminal domain with the enzyme active site. Site-directed mutagenesis of TIMP-1 has demonstrated that the N-terminal amino acids, His7 and Gln9, are important for inhibition.
...
PMID:Structure-function relationships in the tissue inhibitors of metalloproteinases. 795 54

One of the most consistent observations in abdominal aortic aneurysm (AAA) disease is the disorganization and disruption of elastin and other matrix components of the aortic wall. The enzymatic basis for the biochemical features of AAA has been investigated beginning with the demonstration on substrate gel enzymography of a typical "profile" of proteinase activities in AAA tissue extracts which degrade gelatin, casein and elastin. A recombinant TIMP-1 affinity column was developed and three of the elastolytic/caseinolytic activities with approximate molecular weights of approximately 80 kDa, approximately 50 kDa and approximately 32 kDa were partially purified from these extracts. Affinity for rTIMP-1 suggests that these enzymes are members of the matrix metalloproteinase (MMP) family. High molecular weight forms of two MMPs, collagenase (MMP-1) and stromelysin-1 (MMP-3), were also isolated from the AAA tissue on this column; active forms of MMP-1 could be demonstrated by immunoblotting techniques in this preparation under reducing conditions. Infiltrating inflammatory cells are known sources of these proteolytic activities; analysis of these cell populations in the aneurysmal aortic wall using fluorescence-activated cell counting revealed a fifty-fold increase in macrophages (a well-known source of matrix-degrading enzymes) as well as a significant increase in lymphocytes.
...
PMID:Matrix metalloproteinases in abdominal aortic aneurysm: characterization, purification, and their possible sources. 795 5

Dysregulated extracellular matrix (ECM) metabolism may contribute to vascular remodeling during the development and complication of human atherosclerotic lesions. We investigated the expression of matrix metalloproteinases (MMPs), a family of enzymes that degrade ECM components in human atherosclerotic plaques (n = 30) and in uninvolved arterial specimens (n = 11). We studied members of all three MMP classes (interstitial collagenase, MMP-1; gelatinases, MMP-2 and MMP-9; and stromelysin, MMP-3) and their endogenous inhibitors (TIMPs 1 and 2) by immunocytochemistry, zymography, and immunoprecipitation. Normal arteries stained uniformly for 72-kD gelatinase and TIMPs. In contrast, plaques' shoulders and regions of foam cell accumulation displayed locally increased expression of 92-kD gelatinase, stromelysin, and interstitial collagenase. However, the mere presence of MMP does not establish their catalytic capacity, as the zymogens lack activity, and TIMPs may block activated MMPs. All plaque extracts contained activated forms of gelatinases determined zymographically and by degradation of 3H-collagen type IV. To test directly whether atheromata actually contain active matrix-degrading enzymes in situ, we devised a method which allows the detection and microscopic localization of MMP enzymatic activity directly in tissue sections. In situ zymography revealed gelatinolytic and caseinolytic activity in frozen sections of atherosclerotic but not of uninvolved arterial tissues. The MMP inhibitors, EDTA and 1,10-phenanthroline, as well as recombinant TIMP-1, reduced these activities which colocalized with regions of increased immunoreactive MMP expression, i.e., the shoulders, core, and microvasculature of the plaques. Focal overexpression of activated MMP may promote destabilization and complication of atherosclerotic plaques and provide novel targets for therapeutic intervention.
...
PMID:Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. 798 8

The role of Oncostatin M (OM), a monocyte/macrophage and T-cell product, in regulating IL-6 expression in fibroblasts of lung or synovial origin was examined in vitro. Although by itself OM had a minimal effect on enhancing IL-6 production by fibroblasts, in combination with IL-1 alpha or PGE2, OM addition resulted in a dose-dependent synergistic enhancement of IL-6 production. This synergistic effect with either IL-1 alpha (5 ng/ml) or PGE2 (10(-7) M) was clearly evident at concentrations of OM of 10, 20 or 50 ng/ml. Levels of IL-6 resulting from OM and IL-1 alpha stimulation could be reduced by indomethacin (10(-6) M) and restored again by also adding PGE2. Northern blots probed for IL-6 mRNA showed cooperative enhancement of steady state levels at 18 hours of stimulation by OM and IL-1 alpha, or OM and PGE2. Probing for mRNA of the metalloproteinase inhibitor TIMP-1 showed that stimulation by OM, IL-1 alpha or PGE2 enhanced TIMP-1 levels. However, OM (alone) or PGE2 or both combined did not elevate the metalloproteinase stromelysin-1 mRNA signals. Analysis utilizing a rat IL-6 promoter-luciferase reporter gene construct showed that OM stimulation resulted in activation of transcription that synergistically enhanced IL-1-induced levels of reporter gene expression. These results show that although OM has minor effects on IL-6 production alone, the combination of OM and other mediators result in markedly enhanced IL-6 production by fibroblasts in vitro.
...
PMID:Interaction between oncostatin M, interleukin 1 and prostaglandin E2 in induction of IL-6 expression in human fibroblasts. 800 32

Cyclosporin A is successfully used in the treatment of scleroderma, a condition with excessive deposition of collagen in the dermis. Cultured human dermal fibroblasts were used as a model to study the effects of cyclosporin A on metalloproteinase expression and activity. Fibroblasts were treated with collagenase inducing agents, phorbol 12-myristate 13-acetate (PMA), cytokines interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha), and the calcium ionophore A23187 in the presence of cyclosporin A under serum-free conditions, and alterations in metalloproteinase expression were studied by Northern hybridization and immunoblotting analyses, and assays for collagenolytic activity. Induction of collagenase expression by PMA and cytokines was enhanced severalfold by 1-10 microM cyclosporin A. Treatment of cells with cyclosporin A alone caused only a minor increase in collagenase mRNA levels. The secretion of immunoreactive collagenase protein and the level of p-aminophenylmercuric acetate activatable collagenase activity were increased by PMA and further enhanced by cyclosporin A. The expression of the other metalloproteinases stromelysin-1, 92-kD gelatinase, and 72-kD gelatinase or metalloproteinase inhibitor TIMP-1 were not affected by cyclosporin A. Time dependence analysis of the expression of the mRNAs for c-jun and junB indicated that the induction of these genes persisted significantly longer in cells treated with both PMA and cyclosporin A than in cells treated with PMA alone. Enhanced induction of collagenase mRNA may thus result from prolonged AP-1 activity. The results indicate that cyclosporin A potently enhances the expression of collagenase in dermal fibroblasts.
...
PMID:Cyclosporin A enhances cytokine and phorbol ester-induced fibroblast collagenase expression. 800 58

Matrix metalloproteinases (MMP) degrade components of the extracellular matrix and the balance between enzyme production and that of their specific tissue inhibitors (TIMPs) is likely to be crucial for menstruation. The temporal expression of messenger (m) RNA for proMMP-1 (interstitial collagenase), proMMP-3 (stromelysin 1), TIMP-1 and TIMP-2 has been examined by Northern analysis in 73 individually-dated endometrial tissue samples from normal women. Thirteen tissues expressed the mRNA for proMMP-3 and mRNA for proMMP-1 was detected in eleven of the same tissues. All of these tissues were from the menstrual (11) or perimenstrual (2) phases. No expression of mRNA for proMMP-1 or -3 was detected between cycle days 4 and 26. By contrast, mRNA for both TIMP-1 and TIMP-2 was detected in all tissue samples. The abundance of mRNA for TIMP-1 was significantly elevated in menstrual tissue compared with tissue from the rest of the cycle. TIMP-2 mRNA expression displayed considerable variability between individual tissues but mean abundance was also higher in menstrual tissue. Menstruation is therefore associated with a perturbation of the balance between the expression of MMPs and their tissue inhibitors which could lead to tissue degradation.
...
PMID:Expression of messenger ribonucleic acid encoding matrix metalloproteinases and their tissue inhibitors is related to menstruation. 801 90

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>