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)

Human umbilical vein endothelial cells (HUVECs) invade collagen gels and establish vascular-like structures within the gel following stimulation with phorbol esters. This process was quantitated by measuring release of radioactivity from gels composed of [3H]collagen. Collagen was steadily degraded over the period of several weeks by phorbol ester-treated cells while little collagenolysis by cells not receiving phorbol ester was noted. Examination of matrix metalloproteinases (MMPs) secreted by HUVECs revealed a prominent induction of interstitial collagenase. Production of the mature forms of gelatinase A was also stimulated, as was the secretion of gelatinase B. Stromelysin was not detected. Two inhibitors of MMPs, the naturally occurring tissue inhibitor of metalloproteinases (TIMP; 10 micrograms/ml) and the synthetic, peptide inhibitor BB-94 (1 microM) were both effective at blocking HUVEC-mediated collagen degradation. Morphological examination of control, PMA-treated HUVECs, as well as PMA-treated HUVECs receiving TIMP or BB-94, revealed that MMP inhibition resulted in a block to invasion and tubule formation within the collagen gels. Similar results for MMP expression and inhibition of tubule formation in vitro were obtained with human dermal microvascular endothelial cells. Examination of collagen proteolytic fragments revealed that both BB-94 and TIMP blocked cleavage of the alpha 1 and alpha 2 chains of type I collagen and the appearance of tropocollagen fragments A and B, demonstrating that the inhibitors were acting directly upon interstitial collagenase. Our results demonstrate that interstitial collagenase is required for angiogenesis in vitro.
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PMID:Interstitial collagenase is required for angiogenesis in vitro. 751 58

The precursor of matrix metalloproteinase 9 (pro-MMP-9) forms a complex with the tissue inhibitor of metalloproteinases (TIMP)-1 through the C-terminal domain of each molecule, and the N-terminal domain of TIMP-1 in the complex interacts and inhibits active MMPs. We have reported that a catalytic amount of MMP-3 (stromelysin 1) activates pro-MMP-9 (Ogata, Y., Enghild, J. J., and Nagase, H. (1992) J. Biol. Chem. 267, 3581-3584). To activate pro-MMP-9 in the complex, however, an excess molar amount of MMP-3 is required to saturate the TIMP-1 in the complex. The aim of this study was to test the hypothesis that the requirement for excess MMP-3 can be circumvented by specific destruction of TIMP-1 by non-target proteinases. We have tested trypsin, plasmin, cathepsin G, neutrophil elastase, and chymotrypsin as possible inactivators of TIMP-1 and found that neutrophil elastase inactivates TIMP-1 in the complex without significant destruction of pro-MMP-9. Once TIMP-1 is inactivated, pro-MMP-9 can be readily activated by a catalytic amount of MMP-3. These results suggest that neutrophil elastase may participate in the connective tissue destruction at the inflammatory sites not only by its direct action on matrix macromolecules but also by rendering pro-MMP-9 in the pro-MMP-9.TIMP-1 complex activable by MMP-3 as well as activating pro-MMP-3.
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PMID:Preferential inactivation of tissue inhibitor of metalloproteinases-1 that is bound to the precursor of matrix metalloproteinase 9 (progelatinase B) by human neutrophil elastase. 762 55

The precursor of matrix metalloproteinase 9 (pro-MMP-9, progelatinase B) noncovalently binds to tissue inhibitor of metalloproteinases (TIMP)-1 through the C-terminal domain of each molecule. We have isolated the proMMP-9.TIMP-1 complex from the medium of human fibrosarcoma HT-1080 cells and investigated the activation processes of the complex by 4-aminophenylmercuric acetate, trypsin, and matrix metalloproteinase 3 (MMP-3, stromelysin 1). The treatment of the proMMP-9.TIMP-1 complex with 4-aminophenylmercuric acetate or trypsin converts proMMP-9 to lower molecular weight species corresponding to active forms, but no gelatinolytic activity is detected. The lack of enzymic activity results from binding of TIMP-1 to the activated MMP-9. The treatment of the proMMP-9.TIMP-1 complex with a possible physiological proMMP-9 activator, MMP-3, does not reveal any gelatinolytic activity unless the molar ratio of MMP-3 to the complex exceeds 1. This is due to the inhibition of MMP-3 by TIMP-1 forming a ternary proMMP-9.TIMP-1.MMP-3 complex. The formation of the ternary complex weakens the interaction between proMMP-9 and TIMP-1, resulting in partial dissociation of the complex into proMMP-9 and the TIMP-1.MMP-3 complex. When MMP-3 is in excess, the propeptide is completely processed, and the full activity of MMP-9 is detected. Similarly, the proMMP-9.TIMP-1 complex inhibits MMP-1 (interstitial collagenase) and in turn renders the proMMP-9 activable by a catalytic amount of MMP-3. These results suggest that formation of the proMMP-9.TIMP-1 complex regulates extracellular matrix breakdown in tissue by switching the predominant MMP activity from one type to another.
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PMID:Steps involved in activation of the pro-matrix metalloproteinase 9 (progelatinase B)-tissue inhibitor of metalloproteinases-1 complex by 4-aminophenylmercuric acetate and proteinases. 762 79

We have investigated the expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) in colorectal cancer by the immunostaining (avidin-biotin peroxidase complex method) and in situ hybridization (ISH). Both MMP-9 enzyme and messenger RNA (mRNA) for MMP-9 were located in tumor cells, neutrophils, monocyte-macrophages and fibroblasts in colorectal cancer tissue. The location of TIMP-1 mRNA was similar to that of MMP-9 mRNA in colorectal cancer tissue. There was a strong correlation between the expression of MMP-9 in tumor cells and liver metastasis. The expression of mRNA for TIMP-1 in stromal cells in cases associated with liver metastasis was significantly higher than that in cases without liver metastasis. However, in tumor cells, predominant expression of MMP-9 mRNA was observed in all cases associated with liver metastasis. These results suggest that MMP-9 might play an important role in hematogenous metastasis in colorectal cancer and that the balance between the production of MMP-9 and TIMP-1, in particular in tumor cells, is important as one of the pathogenesis of tumor metastasis.
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PMID:[Significance of MMP-9 and TIMP-1 production during liver metastasis in colorectal cancer]. 763 24

Many cellular properties are influenced by the surrounding environment of extracellular matrix. To better define the interaction between mononuclear phagocytes and the extracellular matrix components they contact, we studied the effect of various matrices on the biosynthesis and secretion of metalloenzymes and the tissue inhibitor of metalloproteinases in human alveolar macrophages. We found that native and denatured collagen types I and III markedly augmented production of interstitial collagenase (> 25-fold) and increased tissue inhibitor of metalloproteinases to a lesser degree (2.5-fold). In contrast, the biosynthesis of another major secreted macrophage metalloproteinase, 92-kDa gelatinase, was unaffected by contact with extracellular matrices. Furthermore, other matrix components (i.e. type IV collagen, laminin, fibronectin, elastin) failed to induce collagenase production. Maximal stimulation of macrophage collagenase production was achieved with 1-5 micrograms/ml (3-15 x 10(-9) M) denatured collagen in contact with cells for 2 h. Increased biosynthesis of collagenase was detected within 24 h of cell contact with native or denatured collagen and was accompanied by marked induction of collagenase mRNA levels. Our studies of signal transduction mechanisms demonstrated that indomethacin decreased gelatin-induced collagenase production by 90%, with enzyme levels completely restored by the addition of exogenous prostaglandin E2. Prostaglandin E2 was only effective when added within the first 2 h after indomethacin treatment. These results indicate that extracellular matrix can directly influence its remodeling and repair via regulation of the production of metalloenzymes by resident inflammatory cells. Furthermore, matrix-metalloproteinase inductive interactions are both enzyme- and matrix-specific, and are mediated, at least in part, by a prostaglandin-dependent mechanism.
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PMID:Induction of macrophage metalloproteinases by extracellular matrix. Evidence for enzyme- and substrate-specific responses involving prostaglandin-dependent mechanisms. 768 37

The present study was undertaken to determine the role of the metalloproteinase MMP-9 in the invasive phenotype of squamous-cell carcinoma of the oral cavity and the regulation of its expression. Zymographic analysis of conditioned medium from 2 highly invasive squamous-cell-carcinoma cell lines indicated large amounts of an enzyme which was indistinguishable, in size (92 kDa) from the MMP-9 pro-enzyme. Conversion of the 92-kDa gelatinase into a lower-molecular-weight species (84 kDa), identical in size to the activated gelatinase, was evident when both cell lines, which are avid secretors of urokinase, were cultured in the presence of plasminogen. Penetration of an extracellular-matrix-coated filter was dramatically reduced in the presence of the collagenase inhibitor, tissue inhibitor of metalloproteinase-2, suggesting a critical role for MMP-9 in the invasive process. Immunohistochemical studies demonstrating the presence of MMP-9 in tumor cells of resected squamous-cell cancers suggested that secretion of this collagenase by cells in vitro was reflective of the in vivo setting. Since several phorbol-ester response elements are present in the MMP-9 promoter, we determined the role of protein-kinase-C pathways in the regulation of MMP-9 expression in cultured SCC. Treatment of cells with PMA resulted in a more-than-20-fold increase in the level of protein and mRNA. Conversely, culturing of cells in the presence of the protein-kinase-C inhibitor, calphostin-C, led to a dose-dependent decrease in the amount of MMP-9 mRNA and protein, suggesting that the constitutive expression of this collagenase reflects activation of this signal transduction pathway. In summary, our data suggest that, for a sub-population of squamous-cell carcinomas, secreted MMP-9 is an important determinant of the invasive phenotype, and that the expression of this metalloproteinase is regulated by protein-kinase-C pathways.
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PMID:Role and regulation of expression of 92-kDa type-IV collagenase (MMP-9) in 2 invasive squamous-cell-carcinoma cell lines of the oral cavity. 768 50

The regulatory effect of endogenously synthesized eicosanoid metabolites on the expression of tissue inhibitor of metalloproteinases (TIMP), interstitial collagenase, and 92-kDa gelatinase by human macrophages was examined. TIMP and metalloproteinase production were stimulated with three agonists that produce distinct patterns of eicosanoid synthesis: lipopolysaccharide (10 micrograms/ml), denatured collagen (10 micrograms/ml), or zymosan (1 mg/ml). Indomethacin (3 micrograms/ml) or MK886 (3 microM), a specific inhibitor of 5-lipoxygenase, was used to examine the role of endogenous metabolites of arachidonic acid. Regardless of the agonist used, TIMP production by macrophages was inhibited 65% by indomethacin, synthesis of interstitial collagenase was reduced 70%, and expression of 92-kDa gelatinase was decreased 40%. In contrast, inhibition of leukotriene synthesis had no effect on metalloproteinase or TIMP production. The agonist-stimulated increase in TIMP and collagenase production was directly correlated to the cumulative prostaglandin E2 level induced by the agonist used. However, if response to an agonist was poor, the exogenous addition of prostaglandin E2 could not increase TIMP or collagenase production more than twofold, indicating an important permissive effect of the agonist on the regulation of each protein's expression. The mechanism of indomethacin inhibition of TIMP and collagenase production was studied by labeling the cells with [35S]-methionine and performing immunoprecipitation using specific antiserum. Indomethacin markedly inhibited the lipopolysaccharide-induced biosynthesis of both TIMP and collagenase. Northern analysis revealed parallel suppression of TIMP and collagenase steady-state mRNA levels by indomethacin, indicating pretranslational control. The regulation of inflammatory-cell TIMP and interstitial collagenase expression by prostaglandin E2 suggests that therapy inhibiting the cellular response to prostaglandins may be useful in cutaneous and systemic disease states involving macrophage-mediated connective-tissue destruction.
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PMID:Agonist-induced expression of tissue inhibitor of metalloproteinases and metalloproteinases by human macrophages is regulated by endogenous prostaglandin E2 synthesis. 779 41

The balance between matrix deposition and tissue turnover is fundamental in wound healing. It is likely that the balance between proteolytic enzymes and their inhibitors contributes to this balance. Matrix metalloproteinases are clearly important in tissue turnover, but their roles in wound healing are poorly understood. To investigate this, fluid from healing wounds resulting from mastectomies was collected from 1 h to 10 d post-surgery, and was analyzed for tissue inhibitor of metalloproteinases-1 concentrations. In all cases, tissue inhibitor of metalloproteinases-1 levels were initially comparable to those in serum, but increased rapidly to significantly higher levels within two days, with a tenfold average increase for five patients. On the other hand, zymography revealed that gelatinase A (72 kDa) levels increased moderately, whereas gelatinase B levels (92 kDa) decreased an average of twofold within 4 d. In contrast, fluid from chronic wounds had significantly more gelatinolytic activity, including lower-molecular-weight proteinase species that may represent activated or superactivated gelatinase fragments, as suggested by immunoprecipitation with specific antibodies. Tissue inhibitor of metalloproteinases-1 levels were lower in chronic than in healing wounds. These data may indicate that excess proteolysis in chronic wounds retards successful healing, and results from an imbalance of proteinase and inhibitors, as well as the presence of higher levels of activated metalloproteinases.
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PMID:Tissue inhibitor of metalloproteinases-1 is decreased and activated gelatinases are increased in chronic wounds. 782 79

The matrix metalloproteinase 92-kDa gelatinase is a major product of inflammatory cells. Macrophages synthesize and secrete this proteinase as a proenzyme in association with tissue inhibitor of metalloproteinases (TIMP) (92TIMP), whereas neutrophils store and release it from secondary granules as a TIMP-free proenzyme (92TIMP-free). Metalloproteinase proenzymes can be activated in vitro by a variety of agents, including organomercurials and proteinases, resulting in loss of an 8-10-kDa NH2-terminal domain which disrupts the interaction of a conserved cysteine residue with the catalytic zinc molecule. We report that the activation and processing of 92-kDa gelatinase differs depending on its association with TIMP and the nature of the activating agent. We observed that 92TIMP undergoes classic activation to 82 kDa by stromelysin, whereas exposure to 4-aminophenylmercuric acetate (APMA) results in a final product of 83 kDa that still contains the "prodomain" cysteine. Association with TIMP appears to stabilize the COOH-terminal domain, whereas 92TIMP-free is converted by APMA to a final product of 67 kDa lacking the COOH-terminal portion. In the continued presence of APMA, which maintains cysteine-zinc disruption, the 67-kDa species is at least as active as the classic 82 kDa. In contrast, activation of 92TIMP-free by stromelysin initially generates the 82-kDa form which is followed by final conversion to a 50-kDa species that lacks the catalytic domain of the parent molecule. Therefore, although stromelysin activation of 92TIMP-free is initially efficient, the active 82-kDa form is short-lived and is replaced by an inactive 50-kDa product. This complex pattern of activation of the 92-kDa gelatinase may serve to restrict its proteolytic capacity following exposure to stromelysin and may serve to regulate proteinase activity in vivo.
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PMID:Activation of the 92-kDa gelatinase by stromelysin and 4-aminophenylmercuric acetate. Differential processing and stabilization of the carboxyl-terminal domain by tissue inhibitor of metalloproteinases (TIMP). 789 Jul 73

Monocytes and macrophages can modulate the turnover of extracellular matrix by producing metalloproteinases such as interstitial collagenase and 92-kDa gelatinase as well as tissue inhibitor of metalloproteinases. To study mechanisms of metalloproteinase induction in human mononuclear phagocytes, the effects of direct cell-cell contact between activated T lymphocytes and the human monocytic cell line THP-1 were determined. T cells were first activated with phorbol 12-myristate 13-acetate and phytohemagglutinin for 24 h, fixed with paraformaldehyde, and then exposed to THP-1 cells for 48 h. Upon contact with fixed activated T lymphocytes, a massive induction in the expression of both proteinases and tissue inhibitor of metalloproteinases was observed, whereas unstimulated T cells had no effect. Stimulation of metalloproteinase biosynthesis by THP-1 cells was mimicked by a membrane preparation derived from activated T cell lines, whereas cytosol and nuclear fractions of the T cells were ineffective. Furthermore, activated T lymphocytes exposed to trypsin, tunicamycin, or cycloheximide lost the capacity to stimulate THP-1 cells upon subsequent contact, implying the involvement of cell-surface glycoproteins. Similar induction of metalloproteinases by direct contact with activated T cells was also observed using normal blood monocytes as the target cells, and stimulation of monocyte metalloproteinases by T cell contact occurs at a pretranslational level. Consequently, cell-cell contact may represent an important biological mechanism for potentiating the inflammatory response that leads to extracellular matrix destruction.
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PMID:Direct contact between T lymphocytes and monocytes is a major pathway for induction of metalloproteinase expression. 807 24


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