Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Collagenase production by rodent osteoblasts in response to calciotropic hormones has led to the hypothesis that bone cells play a major role in bone resorption by degrading the surface osteoid layer, thereby exposing the underlying mineralized matrix to osteoclastic action. Many studies suggest, however, that this model might not apply to bone resorption in the human. Human osteoblasts have been shown to produce gelatinase-A (72 kDa) and TIMP-1 (tissue inhibitor of metalloproteinases), but previous investigators have been unable to demonstrate the synthesis of collagenase by human osteoblasts either constitutively or in response to bone resorptive agents. In the present study the ability of human osteoblasts to produce the matrix metalloproteinases (MMPs) collagenase, gelatinase and stromelysin, and their specific inhibitors TIMPs-1 and 2, was examined using highly sensitive and specific antisera and by zymography. Semi-quantitative histomorphometric data showed that cells cultured on either glass or a type I collagen substratum constitutively synthesized gelatinase-A and TIMP-1. On type I collagen, however, a small proportion of unstimulated cells produce both collagenase (7%) and gelatinase-B (95 kDa; 3%). Treatment of cells with either parathyroid hormone (PTH), 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3), or partially purified mononuclear cell conditioned medium (MCM), stimulated the synthesis of collagenase, gelatinase-B and stromelysin; MCM was 2- to 3-fold more potent than either PTH or 1,25(OH)2D3. Zymography using SDS/PAGE on conditioned media from cells cultured on type I collagen films revealed the presence of active gelatinase-A and that MCM stimulated progelatinase-B synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human osteoblasts in culture synthesize collagenase and other matrix metalloproteinases in response to osteotropic hormones and cytokines. 133 77

Several experiments have demonstrated low collagenolytic activity during the development of pulmonary fibrosis. In order to determine if fibroblasts play a role in this alteration, procollagenase and tissue inhibitor of metalloproteinases (TIMP) were quantified in fibroblasts derived from 12 human lung specimens (normal = 6, idiopathic pulmonary fibrosis [IPF] = 6). Under basal conditions, three cell strains from normal and three from fibrotic lung specimens did not synthesize collagenase and a similar number of normal and IPF-derived fibroblast strains produced the enzyme. However, the rate of enzyme synthesis among normal and fibrotic collagenase producing fibroblasts exhibited significant differences. Thus, whereas normal fibroblasts produced more than 300 ng/ml, fibrotic lung fibroblasts secreted approximately half of this amount (115 +/- 67 ng/ml). Phorbol myristate acetate (PMA) enhanced collagenase production in all of the 12 lung fibroblast lines tested. In four IPF fibroblasts, PMA increased collagenase secretion close to those of normal stimulated lung fibroblasts; however, a lower induction was observed in cell strains from two fibrotic lung specimens. There was a wide variation in TIMP production both in normal and fibrotic lung fibroblasts, and no statistically significant difference was observed. Under basal conditions, TIMP levels ranged from 329 to 16,911 ng/ml in normal lung cells, and from 377 to 17,557 in fibrotic lung fibroblasts. PMA induced a severalfold increase in all cell lines. These results suggest that there are subpopulations of lung fibroblasts with different potential to produce collagenase and TIMP in vitro, and that the predominance of low collagenase-producing subsets may contribute to the development of fibrosis.
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PMID:Production of collagenase and tissue inhibitor of metalloproteinases by fibroblasts derived from normal and fibrotic human lungs. 139 48

This study was designed to investigate the biochemical mechanisms responsible for the connective tissue changes seen in actinically damaged skin, which is characterized histologically by diminution and ultrastructural alterations of collagen fibrils and deposition of elastotic material in the papillary dermis. We hypothesized that ultraviolet light could stimulate synthesis of interstitial collagenase in the skin, resulting in collagen degradation. Monolayer cultures of human fibroblasts or keratinocytes were irradiated with ultraviolet A (UVA) or ultraviolet B (UVB) radiation and interstitial collagenase or its inhibitor, TIMP (tissue inhibitor of metalloproteinases) assessed in the conditioned medium with Western immunoblots 24 h after irradiation. Northern blot analysis of the irradiated fibroblasts with a cDNA probe representing collagenase was also performed. Cell viability was greater than 90% with all doses of UV radiation studied. A dose-related increase in immunoreactive collagenase was detected in the medium of fibroblasts irradiated with 0-10 J/cm2 of UVA radiation as well as a parallel increase in the collagenase mRNA in the irradiated cells. UVA radiation stimulated collagenase synthesis in both neonatal and adult fibroblasts. TIMP production in UVA-irradiated fibroblasts increased to a lesser degree than did collagenase and its increase did not parallel the increase in collagenase. UVB (0-100 mJ/cm2) did not stimulate collagenase production by fibroblasts. In contrast to the stimulation of collagenase production by fibroblasts, a slight decrease in immunoreactive collagenase was seen in UVA-irradiated keratinocytes. These data suggest that direct stimulation of collagenase synthesis by human skin fibroblasts by UVA radiation may contribute to the connective tissue damage induced by ultraviolet radiation leading to photoaging.
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PMID:Ultraviolet A irradiation stimulates collagenase production in cultured human fibroblasts. 140 2

Transcription of tissue inhibitor of metalloproteinases-1 (TIMP-1), a secreted protein that regulates the activities of the metalloproteinases, collagenase and stromelysin, is activated by serum growth factors. Transient transfection experiments have revealed several regions of cis-acting regulatory sequences involved in the response of the murine TIMP-1 gene to serum. One area is in the vicinity of the promoter, consisting of a non-consensus binding site (5'-TGAGTAA-3' at -59/-53) for transcription factor AP1 and an adjacent 24 bp region of dyad symmetry that contains a PEA3-binding site. A second is an upstream region (-1020 to -780) that acts as an enhancer when linked to a heterologous promoter, and contains a consensus AP1 binding site (at -803/ -797). Gel retardation assays revealed differences between nuclear factors in mouse C3H10T1/2 cells that bound to the TIMP(-59/ -53)AP1 site and a consensus collagenase TRE (TPA-response element). The TIMP(-59/ -53)AP1 site is a promiscuous motif that binds c-Fos/c-Jun AP1 translated in vitro and is an effective competitor for binding of nuclear AP1 factors to the consensus TRE, but in addition it binds factors that do not associate with the consensus TRE. The TIMP(-59/ -53)AP1 motif and the dyad symmetry region stimulated expression from a thymidine kinase promoter in an additive fashion, and competition experiments showed that excess copies of these factor binding sites reduced expression from a reporter plasmid driven by the TIMP-1 promoter. Our data show that binding sites for AP1 and PEA3 transcription factors are involved in the regulation of TIMP-1 transcription, which suggests that the coordinated induction of TIMP-1, collagenase and stromelysin may be achieved through the actions of a shared set of nuclear transcription factors. However, the properties of the TIMP-1(-59/ -53)AP1 motif likely reflect an additional type of transcriptional regulation restricted to TIMP-1.
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PMID:Involvement of AP1 and PEA3 binding sites in the regulation of murine tissue inhibitor of metalloproteinases-1 (TIMP-1) transcription. 142 Mar 63

To examine the role of metalloproteinases in tissue remodeling associated with wound healing, we used in situ hybridization to localize the expression of collagenase and tissue inhibitor of metalloproteinases (TIMP) in samples of pyogenic granuloma. Strong hybridization for collagenase mRNA was detected in basal keratinocytes near the advancing edge of all ulcerative lesions, but no collagenase mRNA was seen in samples without ulceration. Distinct from the sites of collagenase expression, TIMP mRNA was detected in stromal cells and in cells surrounding proliferating vessels. No collagenase mRNA was found in the epidermis of healthy skin, although occasional stromal cells contained collagenase or TIMP mRNAs, and TIMP mRNA was detected in hair follicles and sebaceous glands. Our results suggest that basal keratinocytes adjacent to wounded epidermis are critically involved in matrix remodeling, much more so than adjacent or underlying dermal fibroblasts. Furthermore, as several reports have suggested, TIMP may play a role in angiogenesis. Finally, in contrast to findings from other models which indicate that collagenase and TIMP proteins are secreted by the same cells, our data also demonstrate that these proteins can be produced in vivo independently of each other.
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PMID:Distinct localization of collagenase and tissue inhibitor of metalloproteinases expression in wound healing associated with ulcerative pyogenic granuloma. 143 Feb 17

Vascular endothelial growth factor (VEGF) is a 45kDa secreted peptide that has potent mitogenic activity specific for endothelial cells in vitro and the ability to induce a strong angiogenic response in vivo. In the present study, 24 h treatment with VEGF resulted in a stimulation of expression of the metalloproteinase, interstitial collagenase, at the protein and mRNA levels 2.5-3.0-fold in human umbilical vein endothelial cells but not in human dermal fibroblasts. The dose response curve for collagenase induction was biphasic with the peak stimulatory response obtained by treatment of cells with 10-100 ng/ml (0.2-2 nM) VEGF. The dose response curve for collagenase induction overlapped with, but was not identical to, the response curve for proliferation, which showed VEGF mitogenic activity between < or = 0.1-50 ng/ml (< or = 0.002-1 nM). There was no induction seen in expression of other members of the matrix metalloproteinase family, including the 72kDa type IV collagenase, the 92kDa type V collagenase, or stromelysin. Expression of transcripts for the major metalloproteinase inhibitor, tissue inhibitor of metalloproteinases, was also unaltered by treatment with VEGF (1-200 ng/ml). These studies demonstrate that in addition to stimulating proliferation of endothelial cells, VEGF can also induce the expression of the only metalloproteinase that can initiate degradation of interstitial collagen types I-III under normal physiological conditions. Both responses are likely to contribute to the angiogenic potential of this peptide.
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PMID:Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. 144 17

Explants of human endometrium were cultured to study the release of matrix metalloproteinases (MMPs). Analysis of conditioned media by zymography revealed latent and active forms of collagenase (MMP-1, EC 3.4.24.7), 72-kDa gelatinase A (MMP-2, EC 3.4.24.24), and 92-kDa gelatinase B (MMP-9, EC 3.4.24.35). These proteinases were identified by their M(r), their inhibition by tissue inhibitor of metalloproteinases, and the activation of their zymogens by trypsin or aminophenylmercuric acetate. In the absence of sex hormone, explants released large amounts of enzyme activities, as measured by densitometry of zymograms or in soluble assays. Physiological concentrations of progesterone (10-200 nM) almost totally abolished the release of collagenase, of total gelatinase activity, and of the active form of gelatinase B and largely inhibited the release of the active form of gelatinase A. These effects, which were antagonized by mifepristone (RU 38486), suggest that progesterone restrains endometrial tissue breakdown by blocking the secretion and activation of MMPs.
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PMID:Progesterone regulates the activity of collagenase and related gelatinases A and B in human endometrial explants. 146

We have recently demonstrated that human keratinocytes synthesize and secrete procollagenase and tissue inhibitor of metalloproteinases (TIMP) in culture. We have examined the response of keratinocyte collagenase production to the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), interleukin-1, extracellular matrix proteins and phagocytosis. Collagenase production in keratinocytes was markedly stimulated by TPA and paralleled the morphologic changes induced by the phorbol ester. Synthesis of collagenase increased six- to 34-fold with TPA, whereas the level of TIMP rose only three-fold. Interleukin-1 did not stimulate collagenase production by the keratinocytes, in contrast to its effect on cultured fibroblasts. When keratinocytes were plated on type I or type IV collagen, they synthesized increased amounts of collagenase compared with cells cultured on laminin or in the absence of matrix. TIMP synthesis was not increased by collagen. Finally, phagocytosis of latex beads did not augment collagenase production by the keratinocytes.
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PMID:Synthesis and regulation of keratinocyte collagenase. 148 20

The tissue inhibitor of metalloproteinases (TIMP, M(r) 30,000) is secreted by many cell and tissue types and has been shown to inhibit most secreted mammalian metalloproteinases. In matrix and tissue invasion assays, the inactivation or removal of TIMP enhances invasiveness. However, many of the cells that secrete TIMP also secrete other metalloproteinase inhibitors. By analysis of medium conditioned by various endothelial, mesenchymal, and neural cells on SDS-.substrate-polyacrylamide-inhibitor gels (reverse zymograms), we have detected at least three other distinct inhibitors of metalloproteinases (IMPs). Some or all of these IMPs have been detected in secretions of mouse, rabbit, sheep, and human cells and are all smaller in apparent molecular size than TIMP (IMP-1, M(r) 26,000; IMP-2, M(r) 21,000; IMP-3, M(r) 18,000). These IMPs are not proteolytic degradation products of TIMP nor do they represent nonglycosylated TIMP. The IMPs do not cross-react in the native or denatured state with any of several anti-TIMP antibodies. The IMPs appear to be regulated independently of each other and of TIMP. In vitro, the complex consisting of one of the IMPs, or TIMP, and a metalloproteinase can be dissociated into functional inhibitor and metalloproteinase. Whether this characteristic is significant in vivo is not known. IMP-2 has been purified from several sources and shares sequence homology with TIMP, suggesting that the IMPs and TIMP may constitute a gene family. The most significant characteristic of IMP-2 is that it appears to preferentially inhibit, on a mole:mole basis, the M(r) 68,000 gelatinase rather than collagenase or stromelysin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Secreted inhibitors of metalloproteinases (IMPs) that are distinct from TIMP. 148 40

Extracellular matrix (ECM) remodeling accompanies cell migration, cell-cell interactions, embryo expansion, uterine implantation and tissue invasion during mammalian embryogenesis. We have found that mouse embryos express mRNA transcripts for collagenase, stromelysin and the tissue inhibitor of metalloproteinases (TIMP) and secrete functional ECM-degrading metalloproteinases, including collagenase and stromelysin. These metalloproteinases are inhibitable by TIMP and are regulated during peri-implantation development and endoderm differentiation. The involvement of a controlled proteolytic reaction, dependent on metalloproteinases, during the implantation of mouse embryos is suggested by the secretion of proteinases by trophoblast during its invasive phase and by the reciprocal expression of TIMP in the maternal deciduum. Exogenous TIMP affects the migration of parietal endoderm cells during blastocyst outgrowth in vitro. Taken together, these data suggest that metalloproteinases function in cell-ECM interactions during mammalian development.
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PMID:Expression and function of matrix metalloproteinases in development. 148 58


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