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)

Synovial fibroblasts freshly isolated from the rheumatoid joint are characterized by their marked connective tissue degradative ability. This phenotype includes the ability to secrete large amounts of the matrix-degrading metalloproteinases, collagenase, and stromelysin. We have found that another aspect of this phenotype is the constitutive expression at both protein and mRNA levels of a 92-kD gelatinolytic metalloproteinase, which is not secreted by normal dermal or lung fibroblasts and is immunologically cross-reactive with a type V collagenase expressed by activated macrophages and neutrophils. Expression of this 92-kD metalloproteinase confers upon the fibroblasts the capacity to degrade collagenase- and stromelysin-resistant interstitial elements, such as collagen types IV, V and XI. In contrast to the 92-kD metalloproteinase, a 68-kD gelatinase (type IV collagenase) was expressed by all fibroblast types studied, indicating that its regulation is distinct from that of the 92-kD gelatinase. To identify what cytokines may be important in the induction of the rheumatoid synovial phenotype, including expression of the 92-kD gelatinase, we exposed normal dermal fibroblasts to a number of cytokines including many known or considered likely to be present in rheumatoid synovial fluid and tissue. Although IL-1 beta, tumor necrosis factor-alpha, lymphotoxin, platelet-derived growth factor, and basic fibroblast growth factor were capable of stimulating fibroblasts to secrete collagenase, only tumor necrosis factor-alpha, lymphotoxin, and IL-1 beta were able to induce expression of the 92-kD gelatinase, demonstrating discordant regulation of the two metalloproteinases. Expression of the 68-kD gelatinase was independent of that of the 92-kD gelatinase, as demonstrated at the protein and mRNA levels. Late passage rheumatoid synovial fibroblasts, which no longer constitutively expressed the 92-kD gelatinase, displayed an accentuated response to IL-1 beta when compared to normal dermal fibroblasts. Thus, in addition to IL-1 beta, tumor necrosis factor-alpha or lymphotoxin may contribute to the expression of a specific rheumatoid synovial phenotype in vivo that is associated with progressive matrix destruction.
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PMID:Constitutive expression of a 92-kD gelatinase (type V collagenase) by rheumatoid synovial fibroblasts and its induction in normal human fibroblasts by inflammatory cytokines. 165 48

Hypoxia results in differential expression of specific genes in certain cell types. In endothelial cells, hypoxia activates several genes that are known to be inducible by transcription factor AP-1, including endothelin-1 and platelet-derived growth factor-B (PDGF-B). In this study we demonstrated that other AP-1-inducible genes are activated by hypoxia in these cells, including collagenase IV and c-jun, and sought to correlate the activation of genes by hypoxia with the activation of transcription factor AP-1. Depending upon the type of cell studied, hypoxic exposure resulted in the induction of AP-1 transcription factor DNA-binding activity with wide variations in levels of binding. The magnitude of activation of transcription factor AP-1 by hypoxia did not always strictly correlate with the level of induction of AP-1-inducible genes. This finding indicates a requirement for additional mechanisms of controlling transcription beyond the simple activation of AP-1 factor DNA-binding activity for the activation of AP-1-inducible genes during hypoxia. Hypoxia has been reported to lower the intracellular redox potential. The effect of redox state changes on AP-1 transcription factor activity and on the activation of AP-1-inducible genes was also studied. PDTC, a potent reducing agent, activated the AP-1 transcription factor in HeLa cells, and also resulted in increased accumulation of c-jun mRNA in these cells. In contrast to PDTC-mediated activation of the AP-1 transcription factor and the subsequent induction of the AP-1-regulated c-jun gene, hypoxic activation of AP-1 transcription factor binding to its cognate DNA sequence did not activate the c-jun gene in HeLa cells, thus documenting distinct differences in signals generated by the reducing intracellular microenvironments created by hypoxia and PDTC. These results demonstrate the induction of AP-1 transcription factor activity by hypoxic environments, but suggest that additional factors or cell-specific signals are involved in the regulation of hypoxia-induced genes.
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PMID:Hypoxia induces AP-1-regulated genes and AP-1 transcription factor binding in human endothelial and other cell types. 757 60

The purpose of this investigation was to examine the role that keratinocyte growth factor (KGF) plays in the control of matrix-degrading protease activity in epithelial cells. The culture conditions had a significant effect on cellular responses to the growth factor. In histiotypic culture on porous-polycarbonate membranes, porcine periodontal ligament epithelial cells responded to KGF with increased 92-kDa gelatinase (matrix metalloproteinase [MMP]-9) activity. No such response was observed in cells maintained on plastic plates. Epidermal growth factor and platelet-derived growth factor also increased MMP-9 activity in the histiotypic cultures of epithelial cells. Addition of heparin with KGF produced a further increase in MMP-9 activity, with heparin alone having no effect. Precoating of polycarbonate membranes with matrix components showed that fibronectin and an engineered poly-RGD molecule substrate were required for KGF plus heparin to increase MMP-9 activity. Precoating plastic culture plates with the same proteins did not generate the same response. Concomitant with gelatinase activity, KGF also increased urokinase-type plasminogen activator in the epithelial cells. Thus, KGF appears to be an important regulator of protease secretion in epithelial cells.
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PMID:Keratinocyte growth factor stimulation of gelatinase (matrix metalloproteinase-9) and plasminogen activator in histiotypic epithelial cell culture. 776 70

Several growth factor ligand and receptor gene products have been shown to play roles during preimplantation mammalian development. Genes for insulin-like growth factors (IGFs), transforming growth factors (TGFs), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and receptors for insulin, IGF, PDGF, TGF alpha and epidermal growth factor (EGF) are expressed by early embryos of several species including mouse, rat, cow and sheep. Roles of growth factors during early development have been demonstrated by addition of purified growth factors to culture medium or by molecular genetic techniques that interfere with gene expression. In this way, it has been shown that successful development of the blastocyst is dependent on the action of epidermal growth factor (EGF) and leukaemia inhibitory factor (LIF). Recent experiments show that both LIF and EGF stimulate secretion of urokinase-type plasminogen activator (uPA) and gelatinase B/matrix metalloproteinase-9 (MMP-9) in day 7 mouse blastocyst outgrowths. At the same time, tissue inhibitors of MMPs (TIMPs) are also expressed by embryonic, decidual and uterine tissues during the implantation process. It appears that LIF may act directly or indirectly, by inducing the expression of other cytokines, to regulate the temporal and spatial production and activity of proteases and protease inhibitors to create a favourable environment for implantation.
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PMID:Roles of growth factors during peri-implantation development. 778 59

The migration and proliferation of vascular smooth muscle cells (SMCs) during neointima formation in atherosclerosis and angioplasty restenosis is mediated by certain growth factors and cytokines, one action of which may be to promote basement-membrane degradation. To test this hypothesis further, the effects of such growth factors and cytokines on the synthesis of two basement-membrane-degrading metalloproteinases, namely the 72 kDa gelatinase (MMP-2, gelatinase A) and the 95 kDa gelatinase (MMP-9, gelatinase B) and three tissue inhibitors of metalloproteinases (TIMPs) was studied in primary cultured rabbit aortic SMCs. Expression of the 95 kDa gelatinase was increased by phorbol myristate acetate, foetal calf serum, thrombin and interleukin-1alpha (IL-1alpha); platelet-derived growth factor (PDGF) BB alone had no effect but acted synergistically with IL-1alpha. A selective protein kinase C inhibitor, Ro 31-8220, abolished induction of the 95 kDa gelatinase. In contrast, none of the agents tested modulated the synthesis of the 72 kDa gelatinase. We conclude that maximal up-regulation of 95 kDa gelatinase expression requires the concerted action of growth factors and inflammatory cytokines mediated, in part, by a protein kinase C-dependent pathway. TIMP-1 and TIMP-2 were highly expressed, and their synthesis was not affected by growth factors or cytokines. Expression of TIMP-3 mRNAs was, however, increased by PDGF and transforming growth factor beta, especially in combination. Divergent regulation of gelatinase and TIMP expression implies that either net synthesis or net degradation of basement membrane can be mediated by appropriate combinations of growth factors and cytokines.
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PMID:Divergent regulation by growth factors and cytokines of 95 kDa and 72 kDa gelatinases and tissue inhibitors or metalloproteinases-1, -2, and -3 in rabbit aortic smooth muscle cells. 867 Jan 28

The v-erbA oncogene coding for a mutated form of the thyroid hormone (T3) receptor (TR alpha 1) increased the invasion capacity of the mouse B3.1 glial cell line. This effect was mediated by the induction of platelet-derived growth factor (c-sis/PDGF B), as shown by its inhibition using an anti-PDGF BB antibody. Also, the low invasion capacity of parental B3.1 and c-erbA-expressing cells (B3.1 + TR alpha 1) was enhanced by exogenously added PDGF BB. This effect was independent of the growth-promoting activity of PDGF and unrelated to the secretion of metalloproteinases. All three cell types (parental B3.1, B3.1 + v-erbA, and B3.1 + TR alpha 1) secreted similar high levels of the M(r) 72,000 collagenase IV (A) independently of PDGF. Anchorage-independent cell growth was also enhanced by v-erbA; B3.1 + v-erbA cells but neither parental B3.1 nor B3.1 + TR alpha 1 cells formed foci in soft agar. The effect of v-erbA only happened in the presence of serum, suggesting that some serum factor(s) cooperate with PDGF to overcome the anchorage dependence of B3.1 + v-erbA cells. Supporting this, high doses of exogenous PDGF were much less efficient than serum, and the addition of an anti-PDGF BB antibody blocked only partially the effect of serum. Basic fibroblast growth factor was found to cooperate with PDGF to abolish anchorage dependence. Moreover, B3.1 + v-erbA cells detached and grew in suspension when cultured on plastic dishes. Interestingly, the transformation-competent c-jun and fra-1 oncogenes were induced by v-erbA in serum-free medium and are candidates to mediate v-erbA effects. In summary, our results show that v-erbA induces transformation parameters in the glial B3.1 cell line via an increase in c-sis/PDGF B and probably other mechanisms, suggesting a role for (autocrine) PDGF stimulation in glial cell transformation.
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PMID:v-erbA oncogene induces invasiveness and anchorage-independent growth in cultured glial cells by mechanisms involving platelet-derived growth factor. 883 67

One of the major differences between fetal and adult wound repair is the unique ability of fetal wounds to heal without scarring. Since scar formation is a function of extracellular matrix deposition, the regulation of this component is fundamental in tissue remodeling. In this study, we have characterized the differences in the secretion of matrix-degrading proteases, namely urokinase plasminogen activator and gelatinase A and B, from fetal and neonatal fibroblasts. In addition, we examined the modulation of these protease levels by growth factors known to be important in wound repair. The results indicate that the secretion of these proteases differ significantly between the two cell types. The levels of urokinase plasminogen activator and its inhibitor were notably higher in media conditioned by neonatal fibroblasts in comparison to fetal samples. In contrast, the basal level of gelatinase A was comparable in both cell types, whilst the level of gelatinase B was elevated in the fetal fibroblasts. Transforming growth factor-beta 1 reduced the level of urokinase plasminogen activator and stimulated the secretion of plasminogen activator inhibitor-1 and progelatinase B in both neonatal and fetal fibroblasts. However, only progelatinase A and an activated form of gelatinase B were significantly elevated in fetal fibroblasts. In contrast, platelet-derived growth factor stimulated urokinase plasminogen activator, its inhibitor and both gelatinase A and B, an effect which was more apparent in fetal fibroblasts. This difference in protease regulation may be reflected in the differing rate and quality of tissue remodeling observed during adult vs fetal wound repair.
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PMID:The differential regulation and secretion of proteinases from fetal and neonatal fibroblasts by growth factors. 907 59

1. Changes in the environmental oxygen tension to which cells are exposed in vivo result in physiological and sometimes pathological consequences that are associated with differential expression of specific genes. 2. Low oxygen tension (hypoxia) affects endothelial cellular physiology in vivo and in vitro in a number of ways, including the transcriptionally regulated expression of vasoactive substances and matrix proteins involved in modulating vascular tone or remodelling the vasculature and surrounding tissue. 3. Hypoxia results in the transcriptional induction of genes encoding vasoconstrictors and smooth muscle mitogens (PDGF-B, endothelin-1, VEGF, thrombospondin-1) and genes encoding matrix or remodelling molecules (collagenase IV (MMP-9), thrombospondin-1) and reciprocal transcriptional inhibition of vasodilatory or anti-mitogenic effectors (eNOS). 4. Oxygen appears to signal through a novel haem-containing sensor and signals initiated by this sensor alter the levels and DNA-binding activity of transcription factors such as activating protein (AP)-1, nuclear factor-kappa B and hypoxia-inducible transcription factor-1. 5. The genes encoding vasoactive factors regulated by oxygen tension are themselves also regulated by the vasoactive agent nitric oxide (NO). 6. Nitric oxide and oxygen transduce similar signals (i.e. their absence results in identical patterns of gene expression in endothelial cells and other cell types). 7. Thus, NO can feedback on and modulate signals induced by hypoxia and vice versa. For example, NO, which can act directly on smooth muscle cells as a vasodilator, can also facilitate vasodilation indirectly by reversing the production of vasoconstrictors induced by hypoxia. 8. Short-term exposure of endothelial cells to low oxygen tension results in the elaboration of predominantly vasoconstricting effectors, while longer-term and more severe hypoxic exposure generates factors that can induce smooth muscle proliferation and remodelling. 9. Thus, the endothelial cell response to hypoxic stress can result in two different consequences in the surrounding tissues, depending on the duration of the exposure: short-term exposure causes physiological and reversible modulation of vascular tone and blood flow; chronic hypoxic stress results in irreversible remodelling of the vasculature and surrounding tissues, with smooth muscle proliferation and fibrosis. 10. This dichotomy of responses to hypoxia may explain, in part, both the acute and chronic pathophysiological sequelae of diseases characterized by regional hypoxia, including atherosclerosis, pulmonary hypertension, sickle cell disease and systemic sclerosis (scleroderma).
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PMID:Endothelial cell responses to hypoxic stress. 1090 94

Trachoma, a chronic follicular conjunctivitis caused by infection with Chlamydia trachomatis, is a leading cause of preventable blindness. The blinding complications are associated with progressive conjunctival scarring. Our immunohistochemical studies of conjunctival biopsies from children with active trachoma demonstrated the presence of both humoral and cell-mediated immune responses. Antichlamydial antibodies can neutralize Chlamydiae, block attachment and internalization of the organism, and can produce partial immunity. Our observations suggest a role for T-lymphocytes and cell mediated immunity in the genesis of conjunctival scarring. Conjunctival epithelial cells expressed major histocompatibility complex (MHC) class II antigens which might allow conjunctival epithelial cells to present Chlamydial antigens to T-cells enhancing the immune response. The epithelial cells expressing MHC class II antigens might present autoantigens to T-cells leading to induction of an autoimmune reaction. We have demonstrated that the conjunctival epithelial cells from patients with trachoma expressed interleukin (IL)-1 alpha and IL-1 beta. In addition, we have detected cytoplasmic expression of IL-1 alpha, IL-1 beta, tumor necrosis factor alpha and platelet-derived growth factor by macrophages. These cytokines have the potential to influence the remodeling and fibrosis observed in trachoma. Alterations of extracellular matrix components and collagen metabolism occur in the conjunctival tissue from patients with trachoma. New collagen type V formation was noted in active trachoma and scarred trachoma. The conjunctival tissue from patients with active trachoma contained increased amounts of collagen types I, III and IV. Scarred trachoma is characterized by marked increase in basement membrane--collagen IV and marked decrease in collagen types I and III. In addition, we demonstrated increased activity of gelatinase B and numbers of inflammatory cells containing gelatinase B in trachoma patients suggesting that this enzyme might be involved in matrix degradation and promotion of conjunctival scarring in trachoma.
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PMID:Immunology of trachomatous conjunctivitis. 1148 68

The genes that mediate fibroproliferative lung disease remain to be defined. Prior studies from our laboratory showed by in situ hybridization and immunohistochemistry that the genes coding for tumour necrosis factor alpha, transforming growth factor beta, the platelet-derived growth factor A and B isoforms, and alpha-1 pro-collagen are expressed in fibroproliferative lesions that develop quickly after asbestos inhalation. These five genes, along with matrix metalloproteinase 9, a collagenase found to be increased in several lung diseases, are known to control matrix production and cell proliferation in humans and animals. Here we show by laser capture microdissection that (i) The six genes are expressed at significantly higher levels in the asbestos-exposed mice when comparing the same anatomic regions 'captured' in unexposed mice. (ii) The bronchiolar-alveolar duct (BAD) junctions, where the greatest number of fibres initially deposit, were always significantly higher than the other anatomic regions for each gene. The first alveolar duct bifurcation (ADB) generally was higher than the second ADB, the ADBs were always significantly higher than the airway walls and pleura, and the airway walls and pleura were generally higher than the unexposed tissues. (iii) Animals exposed for 3 days always exhibited significantly higher levels of gene expression at the BAD junctions and ADBs than animals exposed for 2 days. To our knowledge, this is the first demonstration of a dose-response to a toxic particle in situ, and this response appears to be dependent on the number of fibres that deposits at the individual anatomic site.
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PMID:Laser capture microdissection reveals dose-response of gene expression in situ consequent to asbestos exposure. 1803 78


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