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)

Stromelysin-1, a tissue-remodelling metalloproteinase synthesized by fibroblasts, has proteolytic activity against a variety of extracellular matrix components. Stromelysin-1 gene transcription is induced by the inflammatory cytokine interleukin (IL)-1. In fibroblasts transiently transfected with constructs containing 5'-deletion mutants of the human stromelysin-1 gene promoter, IL-1-induced transcriptional activity was abolished with the removal of region -102 to -54. This region includes an AP-1 binding site at positions -70 to -64. The AP-1 site alone increased the basal activity of and conferred minimal IL-1 inducibility onto the heterologous gene promoter of thymidine kinase. Interestingly, although the removal of the AP-1 site from the native promoter (-1303 to +4) affected the absolute levels of IL-1-induced and basal promoter activity, it did not alter their ratio, indicating the involvement of regions outside the AP-1 site in the IL-1 response. Of the stromelysin-1 5' flanking sequence examined, only the region -274 to -54 could confer IL-1 inducibility to a heterologous promoter independently of the AP-1 site. This region also bound specific nuclear factors. Further analysis revealed that the region composed of -86 to -71 and -63 to -54 could independently respond to IL-1 and bind protein of whole cell extracts. Protein binding to this region and to the AP-1 site was modestly induced by IL-1 treatment. From these results we conclude that, in fibroblasts, the AP-1 site (-70 to -64) is not necessary for the IL-1 response; however, it probably interacts through protein associations with the responsive region immediately surrounding it in the absolute transcriptional activation of the human stromelysin-1 gene by IL-1.
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PMID:Promoter elements in the transcriptional activation of the human stromelysin-1 gene by the inflammatory cytokine, interleukin 1. 809 99

The aim of this study is to examine the transcriptional regulation of matrix metalloproteinase transin in glomerular mesangial cells responding to inflammatory cytokines and heparin. Northern blot analysis revealed that IL-1 beta preferentially induced transin mRNA. The stimulatory effect was not specific to transin, and upregulation of procollagen alpha 1(IV), laminin B2 and tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNAs was also observed. After IL-1 stimulation, expression of the transin transcript increased progressively for up to 48 hours, differing from the limited induction of procollagen alpha 1(IV) or TIMP-1. When mesangial cells were stimulated by IL-1 beta in the presence of heparin, transin expression was markedly suppressed in a dose-dependent manner. The inhibitory effect of heparin was specific to transin, and induction of procollagen alpha 1(IV), laminin B2 or TIMP-1 by IL-1 beta was not affected. These findings revealed the selective counter regulation by IL-1 beta and heparin of the transin expression in mesangial cells.
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PMID:Heparin selectively inhibits gene expression of matrix metalloproteinase transin in cultured mesangial cells. 809 49

The effect of interleukin 1 (IL-1) on equine articular cartilage was investigated, using a cartilage explant culture system. Measurement of [35S]O4 incorporation revealed synthesis of matrix proteoglycan by cartilage to be decreased 45, 59.7, and 37.5% after 1, 3, and 5 days, respectively, in culture in the presence of 5 U of IL-1/ml. There was no change in proteoglycan degradation as determined by measurement of [35S]O4 release into the culture medium. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of cartilage-conditioned medium indicated that exposure of cartilage to IL-1 caused a decrease in total protein synthesis by 45, 68, and 87% after 1, 3, and 5 days, respectively, in culture while selectively inducing synthesis of the 57-kd neutral metalloproteinase stromelysin (matrix metalloproteinase-3) in young and adult horses. Identification of stromelysin was confirmed by functional characterization and immunoprecipitation. Baseline total protein synthesis, as well as specific synthesis of stromelysin in cartilage from adult and aged horses, was markedly less than that of young horses. The IL-1-induced reduction in total protein synthesis may not be a characteristic of equine articular cartilage from affected joints of horses with naturally acquired osteoarthritis as indicated by an overall increase in protein synthesis by osteoarthritic explants. Introduction of IL-1 into an equine articular cartilage explant culture system resulted in decrease of matrix component synthesis and increase in specific degradative enzyme synthesis and activity. Articular cartilage from aged horses had markedly less overall metabolic activity, compared with cartilage from young horses.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of interleukin 1 on articular cartilage from young and aged horses and comparison with metabolism of osteoarthritic cartilage. 814 86

Matrix metalloproteinases (MMPs) play a role in tissue remodelling and angiogenesis. We have investigated the expression and regulation of MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), MMP-7 (matrilysin), MMP-9 (gelatinase B) and their inhibitors TIMP-1 and TIMP-2 in human umbilical vein, femoral vein and microvascular endothelial cells, and compared these data with those obtained with human synovial fibroblasts. Non-stimulated vein endothelial cells expressed the mRNAs for MMP-1, MMP-2, TIMP-1 and TIMP-2. MMP-3 mRNA and protein were undetectable or only weakly expressed, but could be stimulated by the inflammatory mediator tumour necrosis factor alpha (TNF alpha). The expression of MMP-3 and MMP-1 was further enhanced by phorbol 12-myristate 13-acetate (PMA). Phorbol ester also induced TIMP-1 and MMP-9, the expression of the latter being further enhanced by TNF alpha or interleukin 1 alpha (IL-1 alpha). Similar stimulatory effects were observed in microvascular endothelial cells. Hence the inflammatory mediator TNF alpha induces/enhances the production of several matrix metalloproteinases in human endothelial cells. On the other hand, MMP-2 and TIMP-2 were not affected or were affected in a variable way by TNF alpha and/or phorbol ester, suggesting a dissimilar regulation of these proteins. The cyclic AMP-enhancing agent forskolin affected the production of MMPs in a cell-type-specific way. In human vein endothelial cells it enhanced the PMA-mediated induction of MMP-9, whereas it suppressed this induction in human microvascular endothelial cells and in synovial fibroblasts. On the other hand, forskolin suppressed the PMA-mediated induction of MMP-1 and MMP-3 in synovial fibroblasts, while it enhanced or did not affect this induction in various types of human endothelial cells. These observations may have implications for future pharmacological intervention in angiogenesis.
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PMID:Regulation of matrix metalloproteinase expression in human vein and microvascular endothelial cells. Effects of tumour necrosis factor alpha, interleukin 1 and phorbol ester. 828 80

AP-1 is a transcriptional activator composed of homo- and heterodimers of Jun and Fos proteins. It is involved in activation of genes, such as collagenase, stromelysin, IL-2 and TGF beta 1, by tumour promoters, growth factors and cytokines. AP-1 activity is also elevated in response to transforming oncogenes and is required for cell proliferation. AP-1 activity is subject to complex regulation both transcriptionally and post-transcriptionally. Transcriptional control of jun and fos gene expression determines the amount and composition of the AP-1 complex. The jun and fos genes are regulated both positively and negatively and are highly inducible in response to extracellular stimuli. Post translational control is also important. Both cJun and cFos are subject to regulated phosphorylation. In the case of cJun, phosphorylation of sites near the DNA-binding domain inhibits DNA-binding, while dephosphorylation reverses this inhibition. Phosphorylation of cJun on sites within the N-terminal activation domain increases its ability to activate transcription. The protein kinase phosphorylating these sites is stimulated by cytokines and growth factors. Another mechanism modulating AP-1 activity is transcriptional interference by members of the nuclear receptor family and is relevant for the pathophysiology of rheumatoid arthritis (RA). In RA, chronic inflammation leads to increased AP-1 activity in T cells,macrophages and synoviocytes as a response to secretion of cytokines such as IL-1 and TNF alpha. While the IL-2 gene plays a major role in T cell activation, another AP-1 target gene encodes an enzyme, collagenase, responsible for destruction of bone and tendon.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Various modes of gene regulation by nuclear receptors for steroid and thyroid hormones. 831 34

The levels of metalloproteases and inhibitor expression in synovial membranes were measured by analyzing mRNA of collagenase, stromelysin, and tissue inhibitor of metalloproteinase (TIMP-1) in this tissue from 20 healthy persons and 20 patients with osteoarthritis (OA). Our results indicated that while most of the normal synovia expressed TIMP-1 mRNA at low levels, very few expressed metalloproteinase mRNA. In contrast 40% of patients with OA expressed a moderate level of collagenase compared to 55 and 80% cases with considerably elevated stromelysin and TIMP-1 mRNA, respectively. The mRNA expression of collagenase (p < 0.032), stromelysin (p < 0.0001) and TIMP-1 (p < 0.008) was significantly higher in OA than in normals. The greater abundance of stromelysin mRNA relative to collagenase indicates differential regulation of the 2 genes. We also demonstrated an association of IL-1 with metalloproteinase gene expression.
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PMID:Elevated metalloproteinase and tissue inhibitor of metalloproteinase mRNA in human osteoarthritic synovia. 849 67

Catalytic RNA molecules, or ribozymes, have generated significant interest as potential therapeutic agents for controlling gene expression. Although ribozymes have been shown to work in vitro and in cellular assays, there are no reports that demonstrate the efficacy of synthetic, stabilized ribozymes delivered in vivo. We are currently utilizing the rabbit model of interleukin 1-induced arthritis to assess the localization, stability, and efficacy of exogenous antistromelysin hammerhead ribozymes. The matrix metalloproteinase stromelysin is believed to be a key mediator in arthritic diseases. It seems likely therefore that inhibiting stromelysin would be a valid therapeutic approach for arthritis. We found that following intraarticular administration ribozymes were taken up by cells in the synovial lining, were stable in the synovium, and reduced synovial interleukin 1 alpha-induced stromelysin mRNA. This effect was demonstrated with ribozymes containing various chemical modifications that impart nuclease resistance and that recognize several distinct sites on the message. Catalytically inactive ribozymes were ineffective, thus suggesting a cleavage-mediated mechanism of action. These results suggest that ribozymes may be useful in the treatment of arthritic diseases characterized by dysregulation of metalloproteinase expression.
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PMID:Nuclease-resistant ribozymes decrease stromelysin mRNA levels in rabbit synovium following exogenous delivery to the knee joint. 857 Jun 29

Matrix metalloproteinases (MMPs) and interleukin 1 (IL-1) are implicated in inflammation and tissue destruction, where IL-1 is a potent stimulator of connective tissue cells to produce the extracellular matrix-degrading MMPs. Here, we report that IL-1beta, but not IL-1alpha, is degraded by MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), and MMP-9 (gelatinase B). This degradation was effectively blocked by tissue inhibitor of metalloproteinases (TIMP)-1. When IL-1beta was treated with MMPs it lost the ability to enhance the synthesis of prostaglandin E2 and pro-MMP-3 in human fibroblasts. The primary cleavage site of IL-1beta by MMP-2 was identified at the Glu25-Leu26 bond. These results suggest that IL-1beta stimulates connective tissue cells to produce MMPs, but activated MMPs in turn negatively regulate the activity of IL-1beta.
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PMID:Degradation of interleukin 1beta by matrix metalloproteinases. 866 97

Collagens of most connective tissues are subject to continuous remodelling and turnover, a phenomenon which occurs under both physiological and pathological conditions. Degradation of these proteins involves participation of a variety of proteolytic enzymes including members of the following proteinase classes: matrix metalloproteinases (e.g. collagenase, gelatinase and stromelysin), cysteine proteinases (e.g. cathepsin B and L) and serine proteinases (e.g. plasmin and plasminogen activator). Convincing evidence is available indicating a pivotal role for matrix metalloproteinases, in particular collagenase, in the degradation of collagen under conditions of rapid remodelling, e.g. inflammation and involution of the uterus. Under steady state conditions, such as during turnover of soft connective tissues, involvement of collagenase has yet to be demonstrated. Under these circumstances collagen degradation is likely to take place particularly within the lysosomal apparatus after phagocytosis of the fibrils. We propose that this process involves the following steps: (i) recognition of the fibril by membrane-bound receptors (integrins?), (ii) segregation of the fibril, (iii) partial digestion of the fibril and/or its surrounding non-collagenous proteins by matrix metalloproteinases (possibly gelatinase), and finally (iv) lysosomal digestion by cysteine proteinases, such as cathepsin B and/or L. Modulation of this pathway is carried out under the influence of growth factors and cytokines, including transforming growth factor beta and interleukin 1 alpha.
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PMID:Phagocytosis and intracellular digestion of collagen, its role in turnover and remodelling. 876 55

Towards gene transfer-based therapies of renal glomerulonephritis, this study examines the feasibility of using a mesangial cell vector (J. Clin. Invest. 94, 497-505, 1994) engineered to secrete interleukin-1 receptor antagonist (IL-1ra). IL-1ra cDNA was introduced into cultured rat mesangial cells, and stably transfected vector cells were established. Compared to mock transfectants, the vector cells showed blunted expression of gelatinase B, stromelysin and monocyte chemoattractant protein-1 in response to IL-1 beta. The attenuated responses were transferable to untransfected cells by cross-feeding with vector cell-conditioned media. The vector cells were then delivered into the glomeruli of rats via the renal circulation. Compared to either unmodified or mock cell-containing glomeruli, the glomeruli transferred with vector cells showed repressed expression of gelatinase B in response to IL-1 beta. Transfer of vector cells thus conferred insensitivity to IL-1 on the glomerulus. This result indicates the feasibility of modifying glomerular microenvironment against certain pathogenic mediators via the ex vivo transfer of therapeutically-relevant genes to the glomerulus.
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PMID:Gene transfer of interleukin-1 receptor antagonist into the renal glomerulus via a mesangial cell vector. 883 5


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