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)

We have investigated the effect of interleukin 6 (IL-6) on the synthesis of tissue inhibitor of metalloproteinases (TIMP) and matrix metalloproteinases (MMPs), collagenase (MMP-1) and stromelysin (MMP-3) using human skin and uterine cervical fibroblasts. IL-6 did not modulate the expression of MMPs by these fibroblasts, but the production of TIMP was enhanced by IL-6 in a dose dependent manner, whereas IL-1 stimulated the production of both MMPs and TIMP. The combination of IL-6 and IL-1 further augmented IL-1-induced MMPs and TIMP production. The results provide the first evidence that IL-6 participates in the catabolism of the extracellular matrix components by modulating the effects of IL-1 on MMPs and TIMP synthesis as well as its direct effects on the synthesis of TIMP by connective tissue cells.
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PMID:Interleukin 6 enhances the production of tissue inhibitor of metalloproteinases (TIMP) but not that of matrix metalloproteinases by human fibroblasts. 216 9

High levels of collagenase are present in cervical extracts and in the circulation in women at parturition. This study examines the content of collagenase in human placentas at term, the possible contribution to circulating enzyme, and the changes that occur at parturition. Active and latent forms of collagenase are detectable in placentas with apparent relative molecular mass of 60,000 and 65,000 d, respectively. Gel-filtration chromatography was used to identify the presence of excess tissue inhibitor of metalloproteinase as the major collagenase inhibitor in the extracellular matrix of human placentas. After the onset of labor, there was a significant increase in total collagenase activity. Inactivation of the tissue inhibitor of metalloproteinase by reduction of placental extracts with dithiothreitol and alkylation with iodoacetamide resulted in a twelvefold to seventeenfold increase in collagenase activity. Umbilical cord collagenase levels were significantly lower than those in maternal circulation. The possibility of circulating collagenase originating from placenta in labor is discussed.
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PMID:Changes in active and latent collagenase in human placenta around the time of parturition. 216 7

The production of tissue inhibitor of metalloproteinases (TIMP) in human uterine cervical fibroblasts was increased by human recombinant tumor necrosis factor alpha (hrTNF) at a low concentration (0.005 ng/ml) but the elevated synthesis was suppressed in a dose-dependent manner at higher concentrations (up to 50 ng/ml). In contrast, the production of collagenase (EC 3.4.24.7) and stromelysin was stimulated at all the corresponding concentrations. In contrast, human recombinant interleukin-1 alpha (hr IL-1, 10 ng/ml) coordinately induced these enzymes and TIMP production. The reduction of the elevated TIMP production by TNF was not due to the inhibition of TIMP secretion. These results suggest that TNF modulates the extracellular matrix degradation in human fibroblasts bifunctionally by the suppression of TIMP production in addition to the acceleration of matrix metalloproteinases production. Furthermore, the fact that TNF and IL-1 differently controlled the production of TIMP suggests that the signal pathway of TNF for TIMP production is different from that of IL-1.
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PMID:Tumor necrosis factor bifunctionally regulates matrix metalloproteinases and tissue inhibitor of metalloproteinases (TIMP) production by human fibroblasts. 216 46

1. The interaction between interleukin 1 (IL-1) and the fibrinolytic system in the control of collagen degradation by rabbit chondrocytes has been investigated in a tissue-culture system where cells are grown on a 14C-labelled collagen matrix. 2. Culture of rabbit chondrocytes in the presence of human recombinant IL-1 beta at a concentration of 57pM for 48 h led to the presence of procollagenase but not active collagenase in the medium. The latent collagenase could be activated by incubation with an organomercurial, aminophenylmercuric acetate (APMA). 3. Addition of IL-1 beta to chondrocytes grown on a 14C-labelled collagen matrix did not increase the degradation of the matrix compared to control over a 48 h period. However, in the presence of plasmin (200 micrograms ml-1) or plasminogen (100 micrograms ml-1), IL-1 beta (57 pM) caused almost complete degradation of the collagen matrix. Plasmin or plasminogen alone caused only slight degradation of the collagen matrix. 4. Tissue inhibitor of metalloproteinases (TIMP) or the selective metalloproteinase inhibitor, SC44463, inhibited the degradation induced by IL-1 beta and plasminogen in a concentration-related manner and at concentrations that were correlated with inhibition of collagenase. 5. When concentrations of IL-1 beta which caused only minimal degradation of the matrix in the presence of plasminogen were combined with fibrin (1 microgram ml-1), there was almost total degradation of the matrix by 48 h. 6. These results indicate there is a synergistic interaction between IL-1 and the fibrinolytic system in the degradation of collagen by rabbit chondrocytes in culture.
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PMID:Co-operation between interleukin-1 and the fibrinolytic system in the degradation of collagen by articular chondrocytes. 216 39

Orthodontics is based upon the cellular response to biomechanical forces. Unfortunately, however, little is known about the manner in which cells respond to such forces. We have, therefore, devised an experimental model to permit morphologic and metabolic characterization of human cells subjected to a range of cyclic or static mechanical stimuli similar to those which may prevail in orthodontic-orthopedic therapy. This system involves attachment of cells to silicon collagen coated membranes which are then subjected to continuous or cyclic stretching by a motor coupled to a movable supporting frame. Because collagenase is an enzyme likely to play an important role in the ultimate effect of orthodontic forces, we evaluated the impact of biomechanical forces on secretion of this protein in a new experimental model in vitro. We found that cyclic stretching of human fibroblasts over a four day period approximately doubles collagenase production as compared to the control. Continuous stretching, on the other hand, is only 50% as effective in enhancing the enzyme release. In contrast, secretion of the inhibitor of metalloproteinases (collagenase inhibitor) is uneffected by either form of mechanical forces. Thus, the mechanical forces applied upon fibroblasts in this system promote gene expression in favor of matrix degradation. This model, we believe, will offer major insights into the cellular basis of orthodontics.
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PMID:[A new experimental approach to the study of mechanical force in orthodontics]. 216 86

Interferon-gamma (IFN-gamma) is a lymphokine that activates mononuclear phagocytes. To test the hypothesis that IFN-gamma might have important effects upon the ability of human mononuclear phagocytes to degrade extracellular matrix, we have studied the action of this cytokine on the production of metalloproteinases and the counterregulatory tissue inhibitor of metalloproteinases (TIMP) by the human alveolar macrophage. We have found that IFN-gamma potently and selectively suppresses the lipopolysaccharide-induced production of two metalloproteinases--interstitial collagenase and stromelysin--by 50-90% at doses greater than or equal to 10 U/ml. The synthesis of TIMP and 92-kD type IV collagenase was also diminished by IFN-gamma, but these responses required 50- to 100-fold higher concentrations of the cytokine. All doses of IFN-gamma increased total and secreted protein synthesis slightly, indicating a highly specific effect on metalloenzyme biosynthesis. Inhibition of metalloproteinase expression occurred at a pretranslational level, as evidenced by parallel reductions in enzyme biosynthesis and collagenase-specific steady-state mRNA levels. Interestingly, the effect of IFN-gamma on metalloenzyme production was not readily reversible. Therefore, while IFN-gamma activates the macrophage and renders it tumoricidal, this enhanced function appears to be attained at the expense of the cell's capacity to degrade extracellular matrix.
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PMID:Immune modulation of metalloproteinase production in human macrophages. Selective pretranslational suppression of interstitial collagenase and stromelysin biosynthesis by interferon-gamma. 217 Apr 47

In previous studies, elevations in the levels of active and latent collagenase in gingival crevicular fluid (GCF) have been correlated positively with periodontal disease activity. To provide a simple diagnostic approach for testing collagenolytic activity, the feasibility of using a 3.0 ml water mouthrinse to collect GCF simultaneously from all sites in the mouth was assessed. Patients with adult periodontitis (AP, n = 23) and local juvenile periodontitis (LJP, n = 7) were sampled before periodontal therapy and some (12 AP, 4 LJP) were also assessed longitudinally after scaling and root planing, administration of antibiotics, and following periodontal surgery. Healthy patients (n = 19) were used as controls. The levels of active collagenase, procollagenase, and collagenase inhibitor activity were determined by functional assays and quantitated after SDS-PAGE and fluorography. Gelatinase and progelatinase were assayed by enzymography on gelatin-substrate gels. Active collagenase levels were found to be significantly higher (14- to 20-fold) in AP and LJP patients compared to controls, whereas matrix metalloproteinase activity was not detected in mouthrinses from edentulous patients. Collagenase inhibitor levels were generally low in all groups of subjects tested. Following clinical treatment the levels of active collagenase and gelatinase were reduced; the reduction was significant for active collagenase after tetracycline treatment and scaling in LJP patients. Of the clinical indices recorded (gingival index, plaque index, and pocket depth) there were no significant correlations with enzyme activity but similar trends were observed between the changes in active collagenase and gingival index. In patients with untreated periodontal disease, collagenase occurred predominantly in the active form. N-ethylmaleimide (NEM) and p-aminophenylmercuric acetate (AMPA) were equally effective as activators of the latent collagenase, indicating that the collagenase was derived from PMNs, which were also the source of gelatinase. The results of these studies indicate that measurement of active collagenase and gelatinase in mouthrinse samples is potentially useful in the diagnosis and assessment of periodontal disease activity.
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PMID:Identification of polymorphonuclear leukocyte collagenase and gelatinase activities in mouthrinse samples: correlation with periodontal disease activity in adult and juvenile periodontitis. 217 Jun 17

The production of collagenase by human articular chondrocytes in response to interleukin-1 beta is inhibited in a dose-dependent manner by interferon-gamma (1-1,000 units/ml). The analysis of culture medium samples by Western blotting and the measurement of levels of tissue inhibitor of metalloproteinases suggest that the decrease in measurable collagenase activity is primarily due to the inhibition of procollagenase production. These results provide evidence of a role for interferon-gamma in limiting connective tissue degradation.
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PMID:Inhibition of interleukin-1-induced collagenase production in human articular chondrocytes in vitro by recombinant human interferon-gamma. 217 7

Peak (1 and 2 d) and healing (3, 6, and 10 d) inflammatory lesions were produced in rabbits by the topical application of the military vesicant, bis(2-chloroethyl)sulfide, commonly called sulfur mustard (SM). SM produces an acute sterile dermal inflammatory reaction with little or no necrosis, except in the epidermis, which dies during the first day. After an animal was killed, its lesions were excised intact, as full-thickness 1.0-cm2 explants. They were then organ-cultured for 3 d in order to maintain the viability of both local and infiltrating cells. The extracellular fluid in each lesion equilibrated with the culture fluid, which was collected daily and analyzed for collagenase and proteoglycanase activities. These metalloproteinase activities were measured after we had i) destroyed the alpha-macroglobulin inhibitors with KSCN, ii) destroyed the tissue inhibitor of metalloproteinases (TIMP) by reduction and alkylation, and iii) activated the latent proteinase activity with aminophenylmercuric acetate (APMA). Hydroxyproline-containing peptides and glycosaminoglycans (GAG) released into the culture fluids were also measured as indicators of local collagenase and proteoglycanase activity within the inflammatory lesions. In general, the levels of both the metalloproteinases and the products of their activity were higher in second- and third-day culture fluids than in first-day culture fluids, and higher in fluids from SM lesions than in those from normal skin. The activated fibroblast was apparently the major cell type producing the collagenase and proteoglycanase. The hydrolysis of collagen and ground substance occurs pericellularly. An excess of inhibitors exists outside the pericellular region. The daily change in culture fluids apparently decreased such inhibitors, so that by the second and third day of culture we could detect the changes in pericellular enzyme activity that were not detectable on the first day of culture. As the inflammatory lesions healed, the extracellular enzyme products (hydroxyproline and GAG) increased more than the enzymes that produced these products. With healing, a decrease occurs in the extravasation of all serum components, especially the large ones such as the alpha-macroglobulin inhibitors. We propose that during healing, the decrease in these inhibitors allows the metalloproteinases to begin the remodeling process, and that during the peak phase of inflammation, these same inhibitors protect extracellular matrix against hydrolysis by such proteinases.
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PMID:Extracellular collagenase, proteoglycanase and products of their activity, released in organ culture by intact dermal inflammatory lesions produced by sulfur mustard. 217 50

Collagenase has been implicated in colonic anastomotic dehiscence but the enzyme has not previously been specifically measured in colonic healing. A 72 h tissue culture method for colonic tissue and a radiochemical assay for collagenase were adapted to measure the enzyme in healing rabbit colon, with specificity of the assay confirmed by sodium dodecylsulphate polyacrylamide gel electrophoresis. Normal and postoperative colon secreted collagenase, predominantly in a latent form, in the first 24 h of culture. Total activity reached a plateau after 48 and 72 h in culture, when 50-70 per cent of the enzyme was in an active form. At these times in culture, activity was significantly higher than after 24 h (P less than 0.001). One day after anastomosis the total amount of collagenase secreted in culture was higher than normal but the increase did not achieve significance. Three days after anastomosis the colon secreted more collagenase than explants from 1 day postoperative tissue (P less than 0.002). The proportion of active enzyme in the first 24 h in culture was also increased. Since active collagenase can be measured in culture medium from both normal and postoperative colon, the tissue may be secreting plasminogen activator which allows plasmin to activate the enzyme. The increase in collagenase after operation coincided with a decrease in collagen concentration in the colon wall, measured by hydroxyproline. This supports previous suggestions that collagenase contributes to anastomotic dehiscence. However, the findings must be interpreted with caution as the variance of the results was shown to be predominantly due to time in culture, suggesting this could be a bigger influence than the operation itself. In addition, our previously reported immunohistochemical study of this system indicated that collagenase only occurred in a localized region, restricted to the everted portion of the anastomosis, with the activity being tightly controlled by its inhibitor, tissue inhibitor of metalloproteinases.
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PMID:Direct measurement of collagenase in colonic anastomosis. 217 9


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