Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the study was to assess the activities of the collagenases type IV (matrix metalloproteinase type 2 [MMP-2] and matrix metalloproteinase type 9 [MMP-9]), also known as gelatinases, and the local activity of interstitial collagenase (matrix metalloproteinase type I[MMP-1]) in tissue extracts from a case of the botryoid sarcoma, a rare and very malignant tumour of the female genital tract. Zymography revealed that botryoid sarcoma does not express the 92-kDa form of type IV collagenase activity in Triton extract and only weak activity in Heat extract when compared to values found in extracts from striated muscle and fibroma uteri. MMP-1 appeared in the latent form only in the Triton extract of botryoid sarcoma and its activity was lower than those found in the control tissues. These results indicate that the very rapid local invasion and systemic metastases associated with botryoid sarcoma do not depend on the activity of tumour-derived gelatinases.
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PMID:Local activity of matrix metalloproteinases in a case of botryoid sarcoma. 884 7

Human heart matrix metalloproteinases (MMP) are present in the latent form and activated in the failing heart. To examine whether the MMP activation was due to gene and/or post-translational modification, we analysed tissue from 10 explanted hearts due to coronary heart disease (CHD) and five normal left atrial tissue from donor hearts. Based on in situ immunolabeling MMP-1, tissue inhibitor of metalloproteinase (TIMP-1) and collagen were co-localized in the interstitial tissue. Based on sandwich ELISA, TIMP-1 and MMP-1 levels were 37 +/- 8 ng/mg and 9 +/- 2 ng/mg in normal tissue (P < 0.01) and 12 +/- 5 ng/mg and 75 +/- 11 ng/mg in the infarcted tissue (P < 0.01), respectively. These levels suggest repression of TIMP-1 during myocardial infarction. Northern blot analysis indicated that the mRNAs for both MMP-1 and TIMP-1 were increased three-to four-fold in the infarcted tissue as compared to the normal tissue, suggesting upregulation of MMP and TIMP gene transcription following infarction. Based on in situ tissue overlay zymography, the generalized activation of MMP was observed in the interstitium of the infarcted heart. Zymographic and immunoblot analysis demonstrated the presence of one band at 66 kDa (MMP-2) in the normal tissue and several bands at 92 (MMP-9), 66 (MMP-2) and 54 kDa (MMP-1) in the infarcted heart. Incubation of the zymographic gel with metal chelator (phenanthroline) abolished bands at 92 kDa and 54 kDa but phenanthroline did not abolish the lytic band at 66 kDa. The 66 kDa band was completely abolished in the presence of phenanthroline and phenyl methyl sulfonyl fluoride (PMSF). 2D-zymographic analysis suggested that the lytic band at 66 kDa was a mixture of two neutral proteinases with different isoelectric point. Plasminogen/gelatin zymographic analysis of infarcted tissue extract indicated that the band at 66 kDa was plasmin generated due to increased expression of tissue plasminogen activator (tPA) activity. In relation to increased expression of gelatinase in the infarcted tissue, our data suggest that gelatinase B (92 kDa) is induced in diseased heart. The results suggest that tPA converts plasminogen to plasmin which, in turn, activates MMPs and inactivates TIMP-1 post-translationally following ischemic cardiomyopathy.
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PMID:Post-transcriptional regulation of extracellular matrix metalloproteinase in human heart end-stage failure secondary to ischemic cardiomyopathy. 884 29

Previous studies have shown increased susceptibility to periodontal diseases in children with Down's syndrome (DS). The mechanisms involved in the periodontal inflammatory processes in DS are not fully understood. The present study characterized the periodontal status of 9 non-institutionalized DS children 9 to 17 years old (mean 13.6 years) relative to their age-matched systemically and periodontally healthy controls. The periodontal status was assessed by visible plaque index (VPI), gingival bleeding index (GBI), and probing depth. We also assessed, by sodium dodecyl sulphate polyacrylamide gel electrophoresis/laser densitometry and by zymography, the collagenase and gelatinase activities in the gingival crevicular fluid (GCF) and saliva samples collected from DS patients and from the controls. Eight of the nine DS children showed a periodontium comparable to that seen in healthy controls; beginning alveolar bone loss was radiographically seen in the DS patient with deep periodontal pockets. The endogenously active collagenase and total collagenase activities were slightly higher in GCF of DS children compared to healthy controls. Western blot demonstrated that GCF collagenase of DS patients was human neutrophil collagenase (MMP-8 or collagenase-2), which occurred in 75 kDa proMMP-8 and in DS patients, but not in controls, also in 65 kDa active MMP-8 form and occasionally lower 40-50 kDa MMP-8 species. Zymographic analysis revealed the presence of 120 kDa (MMP-9 complexed with neutrophil gelatinase associated lipocalin or NGAL), 92 kDa (MMP-9) and 72 kDa (MMP-2) gelatinases in DS and control GCF. Especially in DS GCF MMP-9 occurred in part in 82-85 kDa activated form. Salivary collagenase in DS was high when compared to controls but of the same MMP-8 type as in control saliva. Our findings suggest that in vivo activated MMP-8 in GCF derived from triggered PMNs and/or cytokine-induced periodontal fibroblasts may reflect periodontal tissue and alveolar bone destruction seen in the early stages of gingivitis/periodontitis associated with Down's syndrome.
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PMID:Characterization of matrix metalloproteinase (MMP-8 and -9) activities in the saliva and in gingival crevicular fluid of children with Down's syndrome. 886 13

The restoration of functional connective tissue is a major goal of the wound healing process. This regenerative event requires the deposition and accumulation of collagenous and noncollagenous matrix molecules as well as the remodelling of extracellular matrix (ECM) by matrix metalloproteinases (MMPs). In this study, we have utilized substrate gel electrophoresis, radiometric enzyme assays, and Western blot analyses to determine the temporal pattern of appearance and activity of active and latent MMPs and their inhibitors during the entire healing process in a partial thickness wound model. Through the use of substrate gel electrophoresis, we studied the appearance of proteolytic bands whose molecular weight was consistent with their being members of the MMP family of enzymes. Proteolytic bands whose molecular weight is consistent with both the active and latent forms of MMP-2 (72 kDa, Type IV gelatinase) were detected in wound fluid of days 1-7 after wounding. The number of active MMP-2 species detectable in wound fluid was greatest during days 4-6 after wounding. The most prominent proteolytic band detected each day migrated with a molecular weight consistent with it being the latent form of MMP-9 (92 kDa, Type V pro-collagenase). In contrast to MMP-2, the active form of this enzyme was never detected. The presence of MMP-1 (interstitial collagenase) was detected by immunoblot in the wound fluid from days 1-6 post-injury. Using a radiometric enzyme assay for collagenase inhibitory activity we have also determined the time course of activity of endogenous matrix metalloproteinase inhibitors. We have correlated these data to the known cellular events occurring in the wound during this time period as well. This study establishes a prototypical pattern of MMP appearance in normal wound healing. It may also provide potential intervention sites for the therapeutic use of inhibitors of aberrant MMP activities which characterize chronic wounds.
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PMID:Temporal study of the activity of matrix metalloproteinases and their endogenous inhibitors during wound healing. 886 13

Human pregnancy is associated with extensive growth and remodelling of the uterus and placenta, and restructuring of these tissues during specific stages of gestation likely involves the degradative activity of various matrix metalloproteinases (MMPs). In this investigation, we used in situ hybridization and immunohistochemistry to identify the sites and cell source of collagenase-1 (MMP-1), stromelysin-1 (MMP-3), matrilysin (MMP-7), and 92 kDa gelatinase (MMP-9), a subgroup of MMPs with the combined ability to degrade essentially all matrix proteins. Human tissues were recovered from uncomplicated pregnancies at various gestational ages and from pregnancies complicated by chorioamnionitis, pre-eclampsia, and placenta accreta. Our results show prominent expression of all four MMPs in specific cells of human placentae involved in trophoblast invasion and placental maturation. Collagenase-1 and stromelysin-1 were detected in cells of the amnion, decidua, and chorionic villi at all stages of pregnancy. Ninety-two kilodalton gelatinase was present in granulocytes whenever present. Matrilysin was seen in cytotrophoblasts and syncytiotrophoblasts during early pregnancy but only in cytotrophoblasts by the third trimester. In addition, we found that matrilysin is over expressed and is produced by more cell types in placentae from pregnancies complicated by pre-eclampsia suggesting that the proteolytic activity of this MMP contributes to the pathology of this condition. We conclude that certain MMPs produced by resident cells of the human placenta, and in particular trophoblasts, participate in the physiological progress human gestation and parturition.
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PMID:Collagenase-I, stromelysin-I, and matrilysin are expressed within the placenta during multiple stages of human pregnancy. 891 3

This study demonstrated the profile of the neutral proteinases, i) matrix metalloproteinases (MMP)-1, -2, -3, and -9, and ii) serine proteinases, elastase, cathepsin G, urokinase and tissue type plasminogen activators (uPA and tPA) as well as their inhibitors, namely, tissue inhibitor of matrix metalloproteinases (TIMP)-1, alpha 1-antitrypsin, alpha 1-antichymotrypsin, plasminogen activator inhibitor (PAI)-1 & 2, around loose hip prostheses to clarify the step in the cascade of biological host response in the loosening of replaced total hip joints. Immunohistochemical analysis showed the presence of MMPs (MMP-1, -2, -3, and -9) and serine proteinases (elastase, cathepsin G, uPA and tPA) both in the interface tissues and pseudocapsular tissues. Functional biochemical analysis revealed elevated proteolytic activities of MMPs, especially, MMP-2 and MMP-9, and also elastase and cathepsin G, which were not inhibited in loco, although the inhibitors, TIMP-1, alpha 1-antitrypsin and alpha 1-antichymotrypsin were detected. The results suggested the imbalance of neutral proteinase-inhibitor levels around loose hip prostheses. The proteolytic enzyme in the interface tissues could directly weaken periprosthetic tissues. The pseudocapsular tissues may induce cellular host response and proteolytic activation. Thus, the pseudocapsular tissues could contribute to the loosening via production of MMPs and serine proteinases into the synovial fluid. Pseudosynovial fluid, which showed high contents of inhibitors (TIMP-1, alpha 1-antitrypsin and alpha 1-antichymotrypsin) associated with low proteolytic potentials, could be produced to prevent the unfavorable elevation of proteolytic enzymes in loco as a local host response to implants.
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PMID:Neutral proteinases and their inhibitors in the loosening of total hip prostheses. 897 33

Both astrocytes in the central nervous system and fibroblasts in somatic tissues are not only the major sources of extracellular matrix components but also of matrix metalloproteinases (MMPs), a family of enzymes directly involved in extracellular matrix breakdown. We have analyzed the regulation of the expression of MMPs and TIMPs (tissue inhibitors of metalloproteinases) in human primary astrocytes stimulated with oncostatin M (OSM) and other extracellular mediators in comparison with normal human dermal fibroblasts. It was found that OSM induced/enhanced transcription of MMP-1 (interstitial collagenase) and MMP-3 (stromelysin 1) in astrocytes, and MMP-1, MMP-9 (gelatinase B), and TIMP-1 in fibroblasts. Analysis of the signal transduction leading to activation of the MMP-1 gene revealed the presence of an OSM-responsive element (OMRE) encompassing the AP-1 binding site and the signal transducer and activator of transcription (STAT) binding element, which mediate activation by OSM. OMRE is also present in the TIMP-1 gene promoter and, although there are some differences in these two motifs, both appear to be targets for the simultaneous action of OSM-induced nuclear effectors. The induced enhancement of transcription by synergistically acting AP-1 and STAT binding elements in response to OSM is Raf-dependent. Cross-talk between the mitogen-activated protein kinase and JAK-STAT pathways is required to achieve maximal induction of the OMRE-driven transcription by OSM.
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PMID:The mitogen-activated protein kinase and JAK-STAT signaling pathways are required for an oncostatin M-responsive element-mediated activation of matrix metalloproteinase 1 gene expression. 899 20

Matrix metalloproteinases (MMPs) and serine proteinases seem to be related to tissue destruction in periodontitis. The presence of MMPs in gingival crevicular fluid (GCF) and saliva, however, has not been studied comprehensively with the enzyme-linked immunosorbent assay (ELISA)-technique. We therefore examined the levels of MMP-1, -3, -8 and -9, and their endogenous inhibitor, tissue inhibitor of matrix metalloproteinases (TIMP-1), in GCF and saliva of patients with adult periodontitis (AP) and localized juvenile periodontitis (LJP). Elevated levels of MMP-1 were detected in LJP GCF compared to AP and control GCF. Elevated levels of TIMP-1 were also detected in LJP GCF in comparison to AP and control GCF. Higher MMP-8 levels were detected in AP GCF compared to LJP and control GCF. The relative low levels of MMP-3 were present in all studied GCF samples. Elevated levels of MMP-8 were further detected in saliva of AP compared to LJP and the controls. Both MMP-1 and TIMP-1 were detected in all studied saliva samples, but not significant differences were detected between the studied groups. Our ELISA-results confirm that (i) PMN MMP-8 and MMP-9 are the main collagenase and gelatinase in AP GCF, whereas GCF collagenase in LJP seems to be of the MMP-1-type; (ii) only low levels of TIMP-1, endogenous MMP-inhibitor, are present in AP GCF, which emphasises the importance of doxycycline as a possible adjunctive drug in the treatment of AP patients; (iii) tests based on specific antibodies against PMN MMPs, especially MMP-8, might serve as a reliable method of measuring and monitoring enzyme levels in GCF from different periodontitis patients.
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PMID:Matrix metalloproteinases and their inhibitors in gingival crevicular fluid and saliva of periodontitis patients. 899 58

Oligodeoxyribonucleoside methylphosphonates (d-OMP) were synthesized whose sequences are complementary to sequences found in the mRNA coding for the 72-kDa (MMP-2) or 92-kDA (MMP-9) forms of human collagenase i.v., matrix metalloproteinases (MMP) whose excessive secretion correlates with the metastatic potential of tumor cells. The effects of these oligomers on MMP-2 and MMP-9 activities secreted by HT1080 cells, a human fibrosarcoma cell line, were studied using a gelatin zymography assay. A d-OMP, M2.3, complementary to nucleotides 14 to 28 of the initiation codon region of MMP-2 mRNA selectively inhibited MMP-2 activity, whereas a d-OMP, M9.1, which was targeted to nucleotides -19 to -5 of the 5'-untranslated region of MMP-9 mRNA selectively inhibited MMP-9 activity over the concentration range 5-50 microM. At 100 microM concentration, both M2.3 and M9.1 inhibited the activities of both MMP-2 and MMP-9. These oligomers were completely stable under cell culture conditions and did not appear to adversely affect cell growth after 48 hours at concentrations up to 100 microM, although 100 microM M9.1 did reduce cell growth 30% after prolonged, 120-hours exposure. Other d-OMP tested either had no effect on collagenase activity or inhibited both MMP-2 and MMP-9 activities. The latter oligomer was complementary to MMP-2 mRNA and partially complementary to MMP-9 mRNA. Oligomer M2.3 was also tested for its effects on the morphology of malignant human lung cells, BZR-T33, growing on the surface of reconstituted base membrane, Matrigel, in culture. In absence of oligomer, the BZR-T33 cells formed extensive networks indicative of the ability of the cells to invade the Matrigel substrate. In the presence of 100 microM M2.3, BZR-T33 formed colonies of rounded cells, a morphology typical of noninvasive cells. Other non-complementary d-OMP had no effect on the morphology of BZR-T33 under these conditions. These results suggest that antisense d-OMP may be useful for inhibiting expression of collagenase in human tumor cells and for studying the role of collagenase expression in tumor cell metastasis.
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PMID:Inhibition of human collagenase activity by antisense oligonucleoside methylphosphonates. 901 63

Tissue destruction during periodontitis is believed to be primarily brought about by leukocyte proteinases. We postulate that oral spirochetes cause discharge of polymorphonuclear leukocyte (PMN) lysosomal enzymes. Effects of Treponema denticola 53-kDa outer membrane protein, lipopolysaccharide (LPS), and peptidoglycan on degranulation of matrix metalloproteinases (MMP)-8 (collagenase) and -9 (gelatinase), cathepsin G, and elastase by human peripheral blood PMNs were studied by specific enzyme assays and Western blot analysis. T. denticola 53-kDa kDa outer membrane protein was found to be a particularly efficient inducer of MMP-8 release. The induction was comparable with that of phorbol myristate acetate, a known inducer of PMN specific granule discharge. All of the treponemal substances, most notably the 53-kDa protein and LPS, induced release of MMP-9, a component of C-type granules. Both collagenase and gelatinase released from PMNs were mostly in active forms. Release of cathepsin G and elastase was also observed with the 53-kDa protein treatment. The other T. denticola substances did not induce release of these serine proteinases. Lactate dehydrogenase was not released from PMNs by the treatments, indicating that the degranulation was specific and not caused by toxic effects of the substances. This was confirmed by transmission electron microscopy of PMNs treated with the 53-kDa protein that showed rapid vacuole formation and cell shape changes but no disintegration of the cells. Thus, T. denticola may participate in the PMN-dependent extracellular matrix degradation during the course of periodontal inflammation by triggering the secretion and activation of matrix metalloproteinases.
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PMID:Membrane components of Treponema denticola trigger proteinase release from human polymorphonuclear leukocytes. 903 54


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