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)

This study examined the presence of extracellular matrix processing enzymes in matrix vesicles produced by rat costochondral resting zone and growth zone chondrocytes in culture. Optimum procedures for the extraction of each enzyme activity were determined. Enzyme activity associated with chondrocyte plasma membrane microsomes was used for comparison. There was a differential distribution of the enzyme activities related to the cartilage zone from which the cells were isolated. Acid and neutral metalloproteinase (TIMP), plasminogen activator, and beta-glucuronidase were highest in the growth zone chondrocyte (GC) membrane fractions when compared with matrix vesicles and plasma membranes isolated from resting zone chondrocyte (RC) cultures. There was a threefold enrichment of total and active acid metalloproteinase in GC matrix vesicles, whereas no enrichment in enzyme activity was observed in RC matrix vesicles. Total and active neutral metalloproteinase were similarly enriched twofold in GC matrix vesicles. TIMP, plasminogen activator, and beta-glucuronidase activities were highest in the plasma membranes of both cell types. No collagenase, lysozyme, or hyaluronidase activity was found in any of the membrane fractions. The data indicate that matrix vesicles are selectively enriched in enzymes which degrade proteoglycans. The highest concentrations of these enzymes are found in matrix vesicles produced by growth zone chondrocytes, suggesting that this may be a mechanism by which the more differentiated cell modulates the matrix for calcification.
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PMID:Matrix vesicles are enriched in metalloproteinases that degrade proteoglycans. 157 46

Endothelial cell stimulating angiogenic factor (ESAF) is an activator of matrix metalloproteinases, including latent collagenase, and is released by chondrocytes during calcification. ESAF, added to cultured growth plate chondrocytes, elicited a time-dependent, 2.4-fold increase in matrix lysis (compared with 30% for IL-1). Matrix breakdown was suppressed by addition of tissue inhibitor of metalloproteinase (TIMP). Although calcification has been previously reported to stimulate ESAF production, no corresponding increase in cartilage lysis was seen in the present study. However, the level of ESAF that cultures produce during calcification is many times less than that added to the cultures in this series of experiments. We conclude that ESAF can produce dramatic increases in cartilage breakdown (apparently by activation of latent enzymes), but only at levels in excess of those stimulated by calcification. This indicates that ESAF may operate in concert with other initiators, perhaps from the invading endothelial cells.
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PMID:Regulation of growth plate cartilage degradation in vitro: effects of calcification and a low molecular weight angiogenic factor (ESAF). 158 5

This study explored whether extracellular matrix processing enzymes are present in matrix vesicles produced by rat costochondral resting zone and growth zone chondrocytes in culture. It was found that there was a differential distribution of enzyme activities related to the cartilage zone from which the cells were isolated. There was a 3-fold enrichment of total and active acid metalloproteinase in growth zone chondrocyte (GC) matrix vesicles whereas no enrichment in enzyme activity was observed in resting zone chondrocyte (RC) matrix vesicles. Total and active neutral metalloproteinase were similarly enriched 2-fold in GC matrix vesicles. TIMP, plasminogen activator and beta-glucuronidase activities were highest in the plasma membranes of both cell types. No collagenase, lysozyme, or hyaluronidase activity was found. The data indicate that matrix vesicles are selectively enriched in enzymes that degrade proteoglycans. The highest concentrations of these enzymes are found in matrix vesicles produced by growth zone chondrocytes, suggesting that this may be a mechanism by which the more differentiated cell modulates the matrix for calcification.
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PMID:Matrix vesicles contain metalloproteinases that degrade proteoglycans. 161 5

We have identified the metalloproteinase inhibitor TIMP-2 as a secreted product of human alveolar macrophages. In contrast to human fibroblasts, TIMP-2 was released from macrophages free of any apparent complexed metalloproteinases. Also in marked distinction to fibroblasts, TIMP-2 secretion from mononuclear phagocytes was subject to modulation by a variety of agents. TIMP-2 was synthesized by macrophages placed in culture under basal conditions in amounts approximately 30% of those secreted by fibroblasts on a per cell basis. The additions of lipopolysaccharide, denatured type I collagen, and zymosan to culture medium each resulted in a dose-dependent and profound decrease in macrophage TIMP-2 protein production and steady-state mRNA levels. In contrast, all of these agents markedly enhanced the biosynthesis of macrophage interstitial collagenase and TIMP-1 as assessed by analysis of identical cell and conditioned media samples. In human fibroblasts, TIMP-2 biosynthesis was unaffected by interleukin-1, tumor necrosis factor-alpha, platelet-derived growth factor, and phorbol ester despite the massive collagenase stimulation induced by each of these agents. We conclude that TIMP-2 is a potentially important mononuclear phagocyte product whose biosynthesis is regulated in a distinct and completely opposite manner to that of collagenase and TIMP-1.
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PMID:Identification of TIMP-2 in human alveolar macrophages. Regulation of biosynthesis is opposite to that of metalloproteinases and TIMP-1. 162 88

Human endothelial cells treated with either interleukin-1 beta, tumor necrosis factor-alpha, or phorbol myristate acetate secreted a metalloproteinase that hydrolyzed and inactivated the two major serine proteinase inhibitors (Serpins) found in plasma, alpha 1-proteinase inhibitor and alpha 1-antichymotrypsin. Surprisingly, the responsible metalloproteinase was identified as human interstitial collagenase (matrix metalloproteinase-1), an enzyme whose only known physiologic substrate has heretofore been believed to be the extracellular matrix molecule, collagen. The metalloproteinase inactivated the Serpins by cleaving peptide bonds at sites unrelated to those hydrolyzed in collagenous macromolecules. NH2-terminal sequence analysis localized the cleavage sites in the Serpins to regions near their respective reactive site centers at three distinct peptide bonds on the amino-terminal side of bulky, hydrophobic residues. Together, these data indicate that matrix metalloproteinase-1 displays an expanded substrate repertoire that supports the existence of a new interface between connective tissue turnover and Serpin function.
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PMID:Interstitial collagenase (matrix metalloproteinase-1) expresses serpinase activity. 164 57

The 72-kd type IV collagenase is a member of the collagenase enzyme family that has been closely linked with the invasive phenotype of cancer cells. Previous studies have shown that both normal cells and highly invasive tumor cells produce the 72-kd type IV procollagenase enzyme in a complexed form consisting of the proenzyme and a novel tissue inhibitor of metalloproteinases, TIMP-2. The balance between activated enzyme and available inhibitor is thought to be a critical determinant of the matrix proteolysis associated with a variety of pathologic processes, including tumor cell invasion. In the present study, we demonstrate that alteration of the metalloproteinase-metalloproteinase-inhibitor balance in favor of excess inhibitor blocks human fibrosarcoma HT-1080 tumor cell invasion of a reconstituted basement membrane. The HT-1080 cell line produces both the 72-kd and the 92-kd type IV collagenases. Alteration of the type IV collagenase-inhibitor balance was achieved by addition of free TIMP-2 or antibodies to 72-kd type IV collagenase. Native, purified TIMP-2 was inhibitory in the range of 1-25 micrograms/mL. Addition of specific antiserum against the 72-kd type IV collagenase, which did not cross-react with the 92-kd type IV collagenase, inhibited HT-1080 cell invasion to the same extent. These results suggest that metalloproteinases, in particular the 72-kd type IV collagenase, are critical for tumor cell invasion of the reconstituted basement membrane. Our findings demonstrate that addition of the endogenous inhibitor TIMP-2 is able to block invasion. Thus, we recommend initiation of in vivo studies of the therapeutic potential of TIMP-2 to block tumor cell invasion and intravasation into the circulation.
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PMID:Tumor cell invasion inhibited by TIMP-2. 204 Oct 46

We address the question as to whether increased metalloproteinase production might be related to the high regional recurrence rate of some carcinomas, and particularly head and neck squamous-cell carcinomas (SCC). Northern blot of total RNA prepared from 26 lung carcinomas, 107 head and neck carcinoma samples and corresponding normal tissue samples demonstrates the frequent and sometimes concomitant over-expression of the 2 stromelysin genes, the type-I collagenase gene and the pump-I gene in the head and neck tumour tissue samples. In these SCC, over-expression of the 2 stromelysin genes and the type-I collagenase gene (but not the pump-I gene) is associated with a high degree of tumour differentiation. Moreover, a tumour with high levels of the stromelysin mRNAs is more likely to show high local invasiveness, suggesting that the stromelysins may be implicated in the clinical course of head and neck tumours. Evaluation of the corresponding mRNA levels may prove a useful indicator for predicting the clinical aggressiveness of these tumours.
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PMID:Expression of collagenase-related metalloproteinase genes in human lung or head and neck tumours. 164 78

A metal-dependent peptidase was isolated from the homogenate of human uterus by standard chromatographic techniques and purified to apparent homogeneity. The peptidase hydrolysed the synthetic vertebrate collagenase substrate 2,4-dinitrophenyl-Pro-Gln-Gly-Ile-Ala-Gly-Gln-D-Arg (Dnp-peptide), the synthetic bacterial collagenase substrate 4-phenylazobenzyloxycarbonyl-Pro-Leu-Gly-Pro-D-Arg (PZ-peptide) and gelatinolytic peptides of gelatin, but was inactive against collagen type I, gelatin and casein. The cleavage site for the Dnp-peptide was the Gly-Ile bond. The enzyme was not only inhibited by metal chelators, such as EDTA, 1,10-phenantroline and dithiothreitol but also by thiol reagents, such as mersalylic acid and N-ethylmaleimid. However, E-64, an inhibitor for thiolproteinases, and leupeptin, an inhibitor for thiol- and serine proteases, did not exhibit any inhibitory activity. Pepstatin, an inhibitor for aspartate proteinases, and inhibitors for serine proteinases like phenylmethanesulfonyl fluoride and Trasylol were ineffective as well. The purified peptidase displayed a single band in the SDS-PAGE with an apparent molecular mass of 65 kDa. Employing isoelectric focusing an IP of 5.0 could be determined. The enzyme's properties are discussed in relation to the proteinase EC 3.4.24.11 and to proteinases of the collagenase family as well as the possibility to discriminate these three metalloproteinase classes by employing the Dnp-peptide.
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PMID:Isolation and properties of a metal-dependent endopeptidase from human uterus hydrolysing synthetic collagenase substrates. 165 Feb 34

Phagocytosis of extracellular collagen by fibroblasts appears to be the principal pathway of collagen degradation in the physiological turnover of connective tissues. To study the mechanism of collagen phagocytosis, subconfluent gingival fibroblasts were serum-starved and incubated for up to 16 h with collagen-coated fluorescent latex beads. Internalization of beads was measured either by flow cytometry or by image analysis. Phagocytosis was blocked by inactivation of protein kinase C with staurosporin, and was also decreased significantly (32%) when cells were pre-incubated for 6h with cycloheximide. Phagocytosis of collagen-coated beads appeared to be receptor-mediated, since internalization was inhibited threefold by the cell-attachment blocking peptide (GRGDSP). The process of internalization was influenced by the type of collagen and its molecular structure. Thus, internalization was decreased in the order: type I greater than V greater than III collagen, and internalization of type I collagen was reduced significantly by digestion with either bacterial (45%) or vertebrate (38%) collagenase. However, collagen denaturation, which facilitates binding to fibronectin, did not effect internalization. Although concanavalin A stimulated both phagocytosis (71%) and collagenase synthesis, PMA and IL-1, which also increase collagenase expression, did not affect phagocytosis, indicating that phagocytosis of collagen-coated beads does not require collagenase. Moreover, analysis of tissue inhibitor of metalloproteinase expression revealed no difference between phagocytic and non-phagocytic cells. Collectively, these results demonstrate that collagen phagocytosis is regulated through protein kinase C and is also dependent upon cellular recognition and collagen structure, but not on the expression of collagenase.
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PMID:Mechanism of collagen phagocytosis by human gingival fibroblasts: importance of collagen structure in cell recognition and internalization. 165 Mar 78

Collagenase is a metalloproteinase that is important in extracellular matrix turnover and is produced by synovial fibroblasts in response to various cytokines and growth factors. Porcine collagenase cDNA was cloned and the sequence shows a 469-amino acid (AA) peptide with high homology to the human and rabbit enzyme (84% and 83.4% respectively). Predicted amino acid sequence from position #99-114 agree well with previously obtained NH2-terminal AA sequence data of purified mature, active pig collagenase. Using the cloned porcine cDNA as a probe in Northern analysis, it was found that IL-1, TNF and EGF enhanced 24-hour steady state mRNA levels while TGF-beta inhibited basal expression of collagenase. When added 10 hours previously, TGF-beta partially inhibited the induction of collagenase by TNF and EGF, but did not affect induction by IL-1.
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PMID:Porcine collagenase from synovial fibroblasts: cDNA sequence and modulation of expression of RNA in vitro by various cytokines. 165 40


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