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)

Transgenic mice were generated that expressed a human collagenase transgene in their lungs under the direction of the haptoglobin promoter. Histological analysis demonstrated disruption of the alveolar walls and coalescence of the alveolar spaces with no evidence of fibrosis or inflammation. This pathology is strikingly similar to the morphological changes observed in human emphysema and therefore implicates interstitial collagenase as a possible etiological agent in the disease process. Although elastase has been proposed as the primary enzyme responsible for emphysematous lung damage, this study provides evidence that other extracellular matrix proteases could play a role in emphysema. In addition, these transgenic mice are a defined genetic animal model system to study the pathogenesis of emphysema.
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PMID:Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema. 145 41

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 studied tissue samples of noninfected delayed union or nonunion of diaphyseal bones in 10 patients immunopathologically and neuroimmunologically 4 to 25 months after the primary injury. Samples mostly consisted of vascularized connective tissue of varying density with the proline-4-hydroxylase-containing fibroblast as the major cell type. Most inflammatory cells were CD4 T-lymphocytes and their number was always twice that of the CD8 positive cells. Staining for CD11b positive monocyte/macrophages showed in all samples positive cells scattered in the connective tissue stroma with perivascular enrichments. Mast cells were absent or very rare. Our findings suggest that delayed union and nonunion tissue consists of vascularized connective tissue, which mostly contains 5B5 fibroblasts, CD11b macrophages and vascular endothelial cells with only few immigrant recently recruited monocytes or lymphoid cells. Almost all resident cells seem to be involved in tissue remodeling as suggested by their content of fibroblast-type MMP-1 and its proteolytic activator MMP-3 or stromelysin. The most striking finding was the paucity or total lack of peripheral innervation, which may have to do with the nonunion of the fracture.
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PMID:Immunologic studies of nonunited fractures. 147

The zymogens of matrix metalloproteinase 1 (MMP-1: tissue collagenase), MMP-2 (gelatinase/type IV collagenase) and MMP-3 (stromelysin) were purified from the culture medium of human rheumatoid synovial fibroblasts and the mechanisms of activation of each zymogen by proteinases and 4-aminophenylmercuric acetate (APMA) were studied by kinetic and sequence analyses. The treatment of proMMP-1 (M(r) = 52,000) with proteinases or APMA converted the zymogen to M(r) = 43,000, but it exhibited only 14-25% of the maximal activity. Incubation of a partially active MMP-1 with MMP-3 resulted in rapid, full activation by generating the 41,000-M(r) MMP-1 with Phe81 as the NH2-terminus. MMP-3 directly activated proMMP-1 by cleaving the Gln80-Phe81 bond, but this reaction was extremely slow, indicating that the Gln80-Phe81 bond is not readily available to MMP-3 in the native proMMP-1 molecule. ProMMP-2 (M(r) = 72,000) was activated only by APMA, but not by proteinases. The activation by APMA was rapid and generated an active MMP-2 of M(r) 68,000, but the enzymic activity declined rapidly after activation by autolysis. The NH2-terminal sequence analysis of active MMP-2 indicated that the Asn80-Tyr81 bond was cleaved upon APMA treatment. In contrast, proMMP-3 (M(r) = 57,000) was activated by a variety of proteinases with different specificities. The initial attacks of these proteinases are on a stretch of highly charged groups at the position 34-39 in the propeptide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation mechanisms of the precursors of matrix metalloproteinases 1, 2 and 3. 148 33

When 12-day rudiments of mouse submandibular glands were cultured, they formed an average two clefts within 24 h. The average number of the clefts, however, increased up to five in the presence of bovine tissue inhibitor of metalloproteinases (TIMP). Contrary to this, either bacterial or bovine interstitial collagenase in the medium completely inhibited the cleft formation of the glands. Electron microscopic observations revealed that the amounts of collagen bundles at the cleft points significantly increased with TIMP, but decreased with bacterial collagenase. These results strongly support the idea that endogenous collagenase regulates the cleft formation through the modulation of fibrillar architectures containing collagen in the extracellular matrix. Recently, our immunohistochemical studies clarified that collagen III, known to be rich in embryonic tissue, accumulated preferentially at the cleft points of the epithelium, and may play a crucial role in submandibular gland morphogenesis.
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PMID:Salivary gland morphogenesis: possible involvement of collagenase. 148 59

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

Rabbit uterine cervical fibroblasts produced a large amount of matrix metalloproteinases (MMPs) such as collagenase (MMP-1) and stromelysin (MMP-3) and a small relatively amount of tissue inhibitor of metalloproteinases (TIMP). When cells were treated with progesterone or oestradiol-17 beta, both steroids concurrently decreased the level of procollagenase and prostromelysin in the culture media and the steady-state levels of the respective mRNAs. On the other hand, the level of TIMP in the culture media and the steady-state level of its mRNA were simultaneously increased by these steroids. Similarly, the suppression of production of MMPs and the augmentation of TIMP production by both steroids were observed with interleukin 1 (IL-1)-treated cells, but the action of progesterone was more effective than that of oestradiol-17 beta in the IL-1-untreated and -treated cells. These results suggest that collagenolysis in uterine cervical fibroblasts is negatively regulated by steroid hormones via the acceleration of TIMP production and the suppression of synthesis of MMPs at the pretranslational level.
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PMID:Hormonal regulation of collagenolysis in uterine cervical fibroblasts. Modulation of synthesis of procollagenase, prostromelysin and tissue inhibitor of metalloproteinases (TIMP) by progesterone and oestradiol-17 beta. 164 18

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 temporal aspects and mechanisms of the regulation of the matrix metalloproteinase (MMP) 72-kDa gelatinase/type IV collagenase (MMP-2) by transforming growth factor-beta 1 (TGF-beta 1) were investigated in early passage human gingival fibroblasts and compared with the regulation of the genes for collagenase (MMP-1) and TIMP, the tissue inhibitor of MMPs. Northern hybridization analyses revealed that 1.0 ng/ml TGF-beta 1 increased the abundance of MMP-2 mRNA/cell approximately 1.5-fold at 24 h, an increase similar to that observed in the level of [35S]methionine pulse-labeled MMP-2 at 24 h (1.9-fold). At 48 and 72 h, the increase in MMP-2 mRNA abundance remained elevated by 1.5-2.2-fold on a per cell basis whereas TIMP mRNA levels were elevated by up to 3.3-fold. In contrast, the relative levels of collagenase mRNA were reduced by 66-75%. The changes in the MMP-2, collagenase, and TIMP mRNA concentrations in response to TGF-beta 1 were blocked by cycloheximide indicating that protein synthesis was required to mediate the effects of TGF-beta 1 on these mRNA levels. TGF-beta 1 was also found to increase the half-life of the MMP-2 mRNA from approximately 46 to approximately 150 h but did not alter the stability of TIMP mRNA (t1/2 approximately 60 h). Nuclear run-off transcription assays revealed that MMP-2 gene transcription was increased approximately 5-fold 7 h following TGF-beta 1-treatment but returned to control levels by 24 h. In comparison, increased TIMP gene transcription was only detectable after 24 h whereas collagenase gene transcription, although low in control cells, was undetectable at 24 h. Gene transcription, mRNA levels, and message stability of the genes for the extracellular matrix proteins type I collagen and fibronectin were also increased by TGF-beta 1. Thus, the similarity in the control of MMP-2, alpha 1 (I) procollagen, and fibronectin expression at the transcriptional and post-transcriptional levels indicates that these genes may share regulatory elements. In comparison, TGF-beta 1 reduced the level of collagenase mRNA and increased the level of TIMP mRNA as a result of altered transcriptional activities, through pathways that required protein synthesis, and without changes in mRNA stability.
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PMID:Transcriptional and post-transcriptional regulation of 72-kDa gelatinase/type IV collagenase by transforming growth factor-beta 1 in human fibroblasts. Comparisons with collagenase and tissue inhibitor of matrix metalloproteinase gene expression. 164 34

Serpins encompass a superfamily of proteinase inhibitors that regulate many of the serine proteinases involved in inflammation and hemostasis. In vitro, many serpins are catalytically inactivated by proteinases that they do not inhibit, leading to the concept of proteolytic down-regulation of serpin inhibitory capacity. The extent to which down-regulation of serpin activity occurs in vivo is debated, since little is known of the rates at which the process occurs. To address this debate, we have measured the rates of inactivation of three serpins, alpha 1-proteinase inhibitor (alpha 1PI), alpha 1-antichymotrypsin (alpha 1ACT), and antithrombin III (ATIII), by three human matrix metalloproteinases (MMPs-1, -2, and -3) thought to be involved in tissue destruction and repair. Our object was to establish a working kinetic model which can be used to predict whether serpin inactivation by these proteinases is likely to occur in vivo. We determined the rates of inactivation of these three serpins by each of the MMPs and compared these to rates of inhibition of the MMPs by an endogenous inhibitor, alpha 2-macroglobulin. An equation designed to predict the extent of substrate hydrolyzed by an enzyme in the presence of an enzyme inhibitor gave the following predictions of the inactivation in vivo: (i) ATIII is unlikely to be inactivated by the MMPs. (ii) MMP-2 (72-kDa gelatinase/type IV collagenase) is unlikely to inactivate any of the three serpins. (iii) MMP-1 (tissue collagenase) will inactivate alpha 1PI and alpha 1ACT only when its concentration saturates that of its controlling inhibitors. (iv) MMP-3 (stromelysin) may inactivate small amounts of alpha 1PI and more significant amounts of alpha 1ACT, even in the presence of its controlling inhibitors. Any physiologic or pathologic inactivation of these serpins by these MMPs that occurs in vivo will probably be due to MMP-3, and will likely only take place in tissues and inflammatory loci where the concentration of MMP inhibitors is depressed.
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PMID:Kinetics and physiologic relevance of the inactivation of alpha 1-proteinase inhibitor, alpha 1-antichymotrypsin, and antithrombin III by matrix metalloproteinases-1 (tissue collagenase), -2 (72-kDa gelatinase/type IV collagenase), and -3 (stromelysin). 165 20


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