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)

Matrix metalloproteinases (MMP) are proteolytic enzymes that play a key role in tissue remodelling during physiological and pathological processes, by initiating the degradation of extracellular matrix. MMP overexpression can lead to tissue destruction which is characteristic of chronic inflammatory diseases such as rheumatoid arthritis and scleritis. Plasma cells are often abundant at such sites of chronic inflammation. In the present study we investigated whether plasma cells could contribute to matrix degradation by their expression of MMP In situ hybridization and immunohistochemical analyses on diseased synovial and scleral tissue demonstrated the expression of stromelysin-1 (MMP-3) and gelatinase B (MMP-9), but little or no tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) mRNA, by IgG-positive plasma cells. Northern blot analysis of RNA extracted from a human plasma cell line (ARH-77), Epstein-Barr virus-transformed B cells, and purified peripheral blood B cells, demonstrated expression of stromelysin mRNA. TIMP-1 mRNA was only detected by the more sensitive reverse transcription PCR method in these cell types. Plasma cells and B lymphocytes cultured in the presence of monensin demonstrated cytoplasmic gelatinase B. Gelatin and casein zymography on conditioned media (CM) derived from cytokine treated plasma cells revealed the induction of secreted gelatinase and stromelysin activity. Western blotting confirmed the presence of stromelysin-1 and TIMP-1 proteins in plasma cell CM. These data suggest that plasma cells are not only capable of modulating an inflammatory response by antibody and cytokine production, but also by their ability to produce MMP. Secretion of MMP from focal aggregates of plasma cells may play a critical role in tissue destructive diseases such as rheumatoid synovitis and scleritis.
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PMID:Expression of matrix metalloproteinases by human plasma cells and B lymphocytes. 964 58

During cutaneous wound healing a number of migratory and remodeling events occur that require the action of matrix metalloproteinases (MMPs) and their natural inhibitors (TIMPs). In this study, we analyzed the temporal and spatial expression patterns of these molecules during the healing of murine excisional skin wounds. Our data imply that defined phases of repair rely on distinct repertoires of MMP activity and TIMP counterregulation. Reepithelialization was found to be associated with active production of collagenase, 92-kDa gelatinase, and stromelysins-1 and -2 by distinct subpopulations of keratinocytes at the migrating border. Notably, no TIMP transcripts were expressed in the epidermis, but TIMP-1 expression in the wound colocalized with expression of collagenase, 92-kDa gelatinase, and stromelysin-1, albeit in distinct cells. Concomitant with the formation of an extensive hyperproliferative epithelium, TIMP-1 transcripts accumulated at the mesenchymal/epidermal border of the granulation tissue. During later phases of wound repair, we observed an increase in 72-kDa gelatinase and MT1-MMP expression, whereby the transcripts of these colocalizing MMPs were detected exclusively and at high levels in the granulation tissue. At completion of reepithelialization, the expression levels of the MMPs and TIMP-1 seen in epidermal and dermal compartments declined to near-basal levels, whereas the macrophage-specific metalloelastase (MME) reached maximum expression. In reepithelialized wound tissue, MME transcripts were detected in deep layers of reconstituted dermis and seemed to cluster around vascular structures. Systemic glucocorticoid treatment, which is known to result in impaired wound healing, led to a nearly complete shut-off of MME expression. These observations imply an additional role of macrophage-related proteolysis, independent of its classical roles during earlier, inflammatory phases of cutaneous wound repair.
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PMID:Matrix metalloproteinases (MMPs) and their physiological inhibitors (TIMPs) are differentially expressed during excisional skin wound repair. 966 17

Biologic activity of IL-1 beta requires processing of the inactive precursor, a function generally ascribed to IL-1 beta-converting enzyme (caspase-1). However, alternative mechanisms of IL-1 beta activation have been postulated in local inflammatory reactions. Expression of IL-1 beta and matrix metalloproteinases (MMPs) frequently occurs simultaneously at sites of inflammation. We describe here that stromelysin-1 (MMP-3), as well as the gelatinases A (MMP-2) and B (MMP-9), processes recombinant human IL-1 beta precursor (pIL-1 beta) into biologically active forms. Detection of both pIL-1 beta processing and biologic IL-1 beta activity demonstrated different processing capacities of the respective MMPs. Conversion of pIL-1 beta by stromelysin-1 required coincubation for at least 1 h, and biologic activity faded after 8 h to 24 h. Gelatinase A was less effective in processing pIL-1 beta, requiring at least 24 h of coincubation. In contrast, gelatinase B processed pIL-1 beta within minutes, resulting in immunoreactive products as well as biologic activity stable for 72 h. In addition, prolonged incubation of mature IL-1 beta with stromelysin-1, and to a lesser extent also with gelatinases, but not with interstitial collagenase, resulted in the degradation of mature IL-1 beta. None of the MMPs processed the second isoform of IL-1, IL-1 alpha. The present study indicates a biphasic regulation of IL-1 beta activity by MMPs: a caspase-1-independent pathway of IL-1 beta activation and inhibition of IL-1 beta activity by degrading the mature cytokine. The balance of the respective MMPs and pIL-1 beta might regulate the long term appearance of IL-1 beta activity at sites of acute or chronic inflammation.
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PMID:Generation of biologically active IL-1 beta by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1 beta processing. 975 50

In order to investigate the regulatory role of only one endometrial cell type on trophoblastic invasion, we explored the effects of culture medium conditioned by in vitro decidualised stromal cells (DCM) and of insulin-like growth factor binding protein-1 (IGFBP-1, the main secretory product of decidual cells) on the trophoblastic secretion of gelatinases and tissue inhibitor of metalloproteinases (TIMP-1). First trimester cytotrophoblastic cells (CTB) were obtained from abortions and cultured in vitro in presence or absence of DCM or IGFBP-1. Secreted gelatinases were analysed in the culture supernatants by zymography and by measurements of the total gelatinolytic activity. Tissue inhibitor of metalloproteinases (TIMP-1) was measured by a commercially available immunoassay. DCM inhibited the total gelatinolytic activity of CTB but increased trophoblastic MMP-9 and TIMP-1. In contrast, IGFBP-1 increased the total gelatinolytic activity and TIMP-1 and had no effect on MMP-2 and MMP-9. We conclude that a factor secreted by decidual cells (possibly TGFbeta) inhibits the total gelatinolytic activity of trophoblast by increasing TIMP-1 but other factors, as yet unidentified, increase MMP-2 and MMP-9 to an extent which does not shift the equilibrium between the gelatinases and TIMP-1 in favour of the gelatinases. In contrast to DCM, IGFBP-1 increases the total gelatinolytic activity probably by stimulating another gelatinase (stromelysin-1?) as MMP-2 and MMP 9 are unchanged by IGFBP-1. The possibility of an integrin mediated effect of IGFBP-1 on CTB is discussed.
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PMID:Involvement of trophoblast in embryo implantation: regulation by paracrine factors. 978 60

A metastatic rat mammary carcinoma cell line, BC1, contains cells that have retained epithelial differentiation characteristics and metaplastic cells that have undergone an epithelial-mesenchymal transition. These two subpopulations cooperate to degrade collagen. We have used novel PCR assays to quantitate, for the first time, absolute levels of the mRNAs encoding matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in cell and tumor samples. BC1 tumors expressed high levels of the collagenase-3, TIMP-2, stromelysin-1, and gelatinase B genes and low levels of the stromelysin-2 and TIMP-1 genes. This pattern of expression was repeated in cultures of BC1 and cultures containing mixed clones of epithelial cells and metaplastic cells. In both BC1 and the biclonal cultures, metaplastic cells were the main source of collagenase-3, stromelysin-1 and stromelysin-2, whereas TIMPs were equally distributed and epithelial cells were the main source of gelatinase B. High levels of all four MMP mRNAs in metaplastic cells were dependent on coculture with epithelial cells, suggesting the production of an inducing factor by the epithelial cells. In contrast, gelatinase B mRNA was produced at a high level by epithelial cells in the absence of metaplastic cells. TIMP-2 mRNA was abundant in both subpopulations grown alone and did not change substantially upon coculture. Thus, the interclonal cooperativity to degrade collagen in BC1 cells required the induction of MMPs in metaplastic cells by epithelial cells. Interclonal cooperativity may be important to the progression of neoplastic tumors, a feature of which is phenotypic heterogeneity.
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PMID:Epithelial cells up-regulate matrix metalloproteinases in cells within the same mammary carcinoma that have undergone an epithelial-mesenchymal transition. 981 7

Neovascularization frequently accompanies chronic immune responses characterized by T cell infiltration and activation. Angiogenesis requires endothelial cells (ECs) to penetrate extracellular matrix, a process that involves matrix metalloproteinases (MMPs). We report here that activated human T cells mediate contact-dependent expression of MMPs in ECs through CD40/CD40 ligand signaling. Ligation of CD40 on ECs induced de novo expression of gelatinase B (MMP-9), increased interstitial collagenase (MMP-1) and stromelysin (MMP-3), and activated gelatinase A (MMP-2). Recombinant human CD40L induced expression of MMPs by human vascular ECs to a greater extent than did maximally effective concentrations of interleukin-1beta or tumor necrosis factor-alpha. Moreover, activation of human vascular ECs through CD40 induced tube formation in a three-dimensional fibrin matrix gel assay, an effect antagonized by a MMP inhibitor. These results demonstrated that activation of ECs by interaction with T cells induced synthesis and release of MMPs and promoted an angiogenic function of ECs via CD40L-CD40 signaling. As vascular cells at the sites of chronic inflammation, such as atherosclerotic plaques, express CD40 and its ligand, our findings suggest that ligation of CD40 on ECs can mediate aspects of vascular remodeling and neovessel formation during atherogenesis and other chronic immune reactions.
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PMID:T lymphocytes induce endothelial cell matrix metalloproteinase expression by a CD40L-dependent mechanism: implications for tubule formation. 991 37

The purpose of this study was to investigate the association among matrix metalloproteinases (gelatinases A and B, stromelysin-3 (ST3) and matrilysin) mRNAs expressed in primary breast carcinomas and standard prognostic parameters and clinical outcome. mRNA levels were determined by Northern analysis in samples of 81 breast cancer patients (median follow-up, 40 months) and 27 samples of uninvolved adjacent breast tissue. Proteases were expressed by the majority of the tumors and normal breast tissues examined. ST3, gelatinase A and matrilysin mRNAs were more often expressed at high levels in carcinomatous than in normal breast tissues. Differences in the distribution of gelatinase B mRNA were not found. However, paired normal tissues generally produced weaker signals when compared to matched tumor samples. Univariate analysis showed no significant association of gelatinase A and matrilysin mRNAs with the classical prognostic markers (age, menopausal status, stage, size, nodal status, vascular infiltrate, necrosis, steroid receptors, metastasis and survival). Overexpression of ST3 was more frequently found in tumors of post-menopausal women (P < 0.022). Elevated expression of gel B mRNA was associated with the presence of vascular infiltrate (P < 0.026), necrosis (P < 0.039), PR negative tumors (P < 0.014) and inversely correlated to the number of survivors (P < 0.021). Multivariate analysis including 68 patients for whom all information was available indicated that neither stromelysin correlated significantly with pathological, clinical or biochemical features. High levels of gelatinase A and B mRNAs were inversely associated with the number of survivors. Our findings suggest that measurements of gelatinase A and B mRNAs expression in breast carcinoma may help to identify patients with an aggressive form of the disease.
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PMID:Expression of gelatinases A and B, stromelysin-3 and matrilysin genes in breast carcinomas: clinico-pathological correlations. 993 4

Matrix metalloproteinases (MMPs) and their natural inhibitors (TIMPs) play an important role in matrix remodelling and their involvement in the formation of scar-like tissue in proliferative vitreoretinopathy (PVR) is unknown. In this study we investigated epiretinal and subretinal membranes of PVR for the presence of selected MMPs and TIMPs whose substrates are extracellular matrix components of these membranes. We examined 23 epiretinal membranes and 15 subretinal membranes of PVR for deposition of interstitial collagenase (MMP-1), stromelysin-1 (MMP-3), gelatinase A (MMP-2), gelatinase B (MMP-9) and two tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) by immunohistochemical methods. Normal cadaveric retinas served as controls. We observed that a large proportion of epiretinal and subretinal membranes stained for MMP-1 and MMP-2, whilst MMP-3, MMP-9, TIMP-1 and TIMP-2 were only observed in a small proportion of specimens. Normal cadaveric retinas stained for MMP-1 but not for MMP-2, MMP-3, MMP-9 or TIMP-1. TIMP-2 positive cells were observed within the inner and outer nuclear cell layers of normal retina. Presence of MMP-2, MMP-3 and TIMP-1 in epiretinal and subretinal membranes of PVR but not in normal retina indicates that these molecules may play an important role during the healing process that follows rhegmatogenous retinal detachment. An understanding of the mechanisms that control production and activity of these enzymes and their inhibitors may aid in the design of new therapeutic approaches to treat and prevent PVR.
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PMID:Predominance of MMP-1 and MMP-2 in epiretinal and subretinal membranes of proliferative vitreoretinopathy. 998 46

We compared the association constants of tissue inhibitor of metalloproteinases (TIMP)-3 with various matrix metalloproteinases with those for TIMP-1 and TIMP-2 using a continuous assay. TIMP-3 behaved more like TIMP-2 than TIMP-1, showing rapid association with gelatinases A and B. Experiments with the N-terminal domain of gelatinase A, the isolated C-terminal domain, or an inactive progelatinase A mutant showed that the hemopexin domain of gelatinase A makes an important contribution to the interaction with TIMP-3. The exchange of portions of the gelatinase A hemopexin domain with that of stromelysin revealed that residues 568-631 of gelatinase A were required for rapid association with TIMP-3. The N-terminal domain of gelatinase B alone also showed slower association with TIMP-3, again implying significant C-domain interactions. The isolation of complexes between TIMP-3 and progelatinases A and B on gelatin-agarose demonstrated that TIMP-3 binds to both proenzymes. We analyzed the effect of various polyanions on the inhibitory activity of TIMP-3 in our soluble assay. The association rate was increased by dextran sulfate, heparin, and heparan sulfate, but not by dermatan sulfate or hyaluronic acid. Because TIMP-3 is sequestered in the extracellular matrix, the presence of certain heparan sulfate proteoglycans could enhance its inhibitory capacity.
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PMID:Human tissue inhibitor of metalloproteinases 3 interacts with both the N- and C-terminal domains of gelatinases A and B. Regulation by polyanions. 1019 61

Evidence presented in the accompanying article (Gibbs, D. F., T. P. Shanley, R. L. Warner, H. S. Murphy, J. Varani, and K. J. Johnson. 1999. Role of matrix metalloproteinases in models of macrophage-dependent acute lung injury: evidence for alveolar macrophage as source of proteinases. Am. J. Respir. Cell Mol. Biol. 20:1145-1154) implicates alveolar macrophage matrix metalloproteinases (MMPs) in two models of acute lung inflammation in the rat. As a prerequisite to understanding which specific MMPs might be involved in the injury and how they might function, it was necessary to know the spectrum of enzymes present. To this end, alveolar macrophages were obtained from normal rat lungs by bronchoalveolar lavage, placed in culture with and without various agonists, and assessed by a variety of techniques for MMPs. The identification process involved characterization by gelatin, beta-casein, and kappa-elastin zymography, with confirmation of identity by Western blot/immunoprecipitation. Message levels of detected MMPs were assessed by Northern blot. Rat alveolar macrophages were found to produce a low constitutive level of MMP-2 (72-kD gelatinase A) that was only modestly upregulated following stimulation with phorbol myristate acetate, bacterial lipopolysaccharide, or immunoglobulin A-containing immune complexes. Although control cells were found to produce little or no MMP-9 (92-kD gelatinase B) or MMP-12 (metalloelastase), both enzymes were markedly upregulated upon stimulation. In the same stimulated macrophages there was little activity against type I collagen (associated with MMP-13 [collagenase-3] on the basis of Western blotting), no activity suggestive of stromelysin or matrilysin, and no measurable secretion of the serine proteinases, elastase and cathepsin G. These data demonstrate the ability of rat alveolar macrophages to elaborate certain MMPs under proinflammatory conditions, consistent with their possible involvement in the progression of acute inflammation.
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PMID:Characterization of matrix metalloproteinases produced by rat alveolar macrophages. 1034 Sep 32


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