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)

Matrix metalloproteinases (MMP) are a family of proteolytic enzymes that mediate the degradation of extracellular matrix macromolecules, including interstitial and basement membrane collagens, fibronectin, laminin, and proteoglycan core protein. The enzymes are secreted or released in latent form and become activated in the pericellular environment by disruption of a Zn(++)-cysteine bond which blocks the reactivity of the active site. The major cell types in inflamed and healthy periodontal tissues (fibroblasts, keratinocytes, endothelial cells, and macrophages) are capable of responding to growth factors and cytokines, as well as to products released from the microbial flora by induction of transcription of 1 or more MMP genes. Cytokines that are likely to regulate expression of MMP genes in periodontal tissues include IL-1, TNF-alpha, and TGF-alpha. In addition, triggered PMN leukocytes which express only 2 MMP (PMN-CL and Mr 92K GL) release these enzymes from specific granule storage sites in response to a number of stimuli. The evidence that MMP are involved in tissue destruction in human periodontal diseases is still indirect and circumstantial. Cells isolated from normal and inflamed gingiva are capable of expressing a wide complement of MMP in culture and several MMP can be detected in cells of human gingiva in vivo. In addition, PMN-CL and Mr 92K GL are readily detected in gingival crevicular fluid from gingivitis and periodontitis patients. Osteoclastic bone resorption does not appear to directly involve MMP, but a body of evidence suggests that bone resorption is initiated by removal of the osteoid layer by osteoblasts by means of a collagenase-dependent process.
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PMID:Role of matrix metalloproteinases in human periodontal diseases. 831 70

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

Interstitial collagenases, including matrix metalloproteinase-1 (MMP-1) and -8 (MMP-8), serve as initiators of extracellular matrix destruction in periodontal disease. Collagenase activities are mainly regulated by tissue inhibitors of metalloproteinases (TIMPs). We tested the effects of inflammation on MMP-1 and MMP-8 gene expression in periodontal disease. To determine the relative abundance of these mRNAs in gingiva, we used a reverse transcription-polymerase chain reaction (RT-PCR) assay. Gingival biopsies were divided into 2 groups; a control group and an inflamed group with severe gingivitis or periodontitis. The MMP-1 mRNA levels were significantly elevated in inflamed gingiva, while the levels of the MMP-8 transcript were not different in the 2 groups and barely detectable by RT-PCR assay. The expression of the TIMP-1 gene was not altered, and remained higher than any of these other genes in both control and diseased gingivae. These results suggest that MMP-1 rather than MMP-8 may play an important role in the initiation of collagen degradation in periodontal disease. However, the possibility remains that MMP-8 plays an important role in periodontal tissue destruction, since the mRNA abundance and not the enzyme activity was assessed.
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PMID:Matrix metalloproteinases-1 and -8 and TIMP-1 mRNA levels in normal and diseased human gingivae. 902 26

The serum protein, alpha 1-proteinase inhibitor (alpha 1-PI), defends the host against serine proteinases, e.g. PMN elastase. Using a rabbit anti-serum against human alpha 1-PI, this protein in GCF was quantified from a standard curve constructed from dot-blot analysis and characterized by Western blot. GCF was collected on filter paper strips from healthy (H), gingivitis (G) and adult periodontitis (AP) patients, then extracted with Tris/NaCl/CaCl2 buffer, pH 7.6. alpha 1-PI concentration increased with G and was highest in AP subjects. H sites only showed intact alpha 1-PI (52 kDa); no degradation fragments (48 kDa) were detected. In G and AP subjects, alpha 1-PI degradation fragments were seen in 17% and 71% of GCF samples, respectively. Both collagenase and alpha 1-PI-degrading activities in GCF increased with severity of inflammation (GCF flow). Moreover, the alpha 1-PI degrading (or serpinolytic) activity was characterized as a matrix metalloproteinase, probably collagenase, based on its in vitro response to a panel of different proteinase inhibitors including doxycycline. We propose: (1) that collagenase promotes periodontal breakdown not only by degrading collagen, but also by depleting alpha 1-PI regulation of elastase and other serine-proteinases, thereby favoring a broader attack on extracellular matrix (ECM) constituents, and (2) based on a recent longitudinal double-blind study using the techniques described above for alpha 1-PI analysis, that low-dose doxycycline administration to humans with adult periodontitis can inhibit this broad cascade of ECM degradation.
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PMID:alpha 1-Proteinase inhibitor in gingival crevicular fluid of humans with adult periodontitis: serpinolytic inhibition by doxycycline. 908 38

Here, we describe the influence of heparin(s) on the interleukin-1-beta (IL-1beta)-induced expression of collagenase (matrix metalloproteinase-1, MMP-1), stromelysin-1 (matrix metalloproteinase-3, MMP-3) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in human gingival fibroblasts (HGF). Amounts of secreted enzymes and inhibitors as well as their mRNA steady-state levels increased significantly following supplementation of HGF culture medium with 2 ng/mL of IL-1 beta1. Addition of heparin to cell culture medium 1 hour following IL-1beta decreased MMP and TIMP-1 expression in a dose-dependent manner. The inhibitory effect of heparin was significant at a concentration as low as 1 microg/mL. These findings could be reproduced with a low Mr heparin fragment devoid of anticoagulant activity. Heparin and fragments might therefore reduce the excessive proteolytic capacity of the gingival fibroblast during inflammation and could be useful as pharmacological agent(s) in gingivitis and periodontitis.
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PMID:Influence of heparin(s) on the interleukin-1-beta-induced expression of collagenase, stromelysin-1, and tissue inhibitor of metalloproteinase-1 in human gingival fibroblasts. 982 76

Neutrophil collagenase (matrix metalloproteinase 8 [MMP-8]) is an important mediator of tissue destruction in inflammatory diseases. Studies of anaerobic periodontal infections have shown that active MMP-8 in gingival crevicular fluid is associated with the degradation of periodontal tissues in progressive periodontitis whereas the latent enzyme is predominant in gingivitis. Since the activation of MMP-8 appears to be a crucial step in periodontitis, we have examined the activation of MMP-8 in gingival crevicular fluid samples by using a soluble biotinylated collagen substrate. Analysis of gingival crevicular fluid in periodontitis, gingivitis, and controls revealed sixfold (P < 0.001)-higher levels of active collagenase in periodontitis (n = 12) samples compared to gingivitis (n = 17) samples, which exhibited low levels of activity, while controls (n = 25) showed no activity. After gingival crevicular fluid was collected, no further activation of latent collagenase occurred in vitro. Although both MMP-1 and MMP-8, but not MMP-13, could be detected by immunoblots, blocking antibodies to MMP-1 showed that collagenase activity was largely contributed by MMP-8, which was localized to the matrix of diseased tissues. The MMP-8 in gingival crevicular fluid migrated primarily as a 60-kDa form with smaller amounts of a 78-kDa species, whereas MMP-8 isolated from peripheral neutrophils migrated at 70 and 89 kDa, corresponding to active and latent forms of the enzyme, respectively. Most of the MMP-8 in the 60- and 70-kDa bands selectively bound to tissue inhibitor of metalloproteinase 2 and collagen, indicating that most, but not all, of the enzyme in these bands was in an activated form. However, the amounts of the 78- and 60-kDa forms from gingival crevicular fluid in different samples did not correlate (r2 = 0.028) with the latent and active enzyme measured by collagenase assay. Collectively, these studies have identified distinct forms of latent and active MMP-8 in gingival crevicular fluid that appear to result from a unique activation mechanism that occurs in periodontitis. The complexity of MMP-8 activation is further indicated by the presence of latent, activated, and superactivated forms of MMP-8 in the 60- and 70-kDa bands obtained from gingival crevicular fluid and neutrophil samples, respectively.
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PMID:Activation of neutrophil collagenase in periodontitis. 1022 90

Heparin present in tissue has been reported to be a potential locally active agent responsible for bone resorption by the stimulation of collagenase via osteoclast activation and increased collagenase synthesis by the osteoblast. The purpose of this study was to extract, identify and quantify heparin in the "clinically normal", mildly and severely inflamed gingiva of Beagle dogs, using a simple and reliable technique. The extraction was carried out by homogenization, fat elimination, proteolytic digestion and precipitation, with organic solvents. Identification was performed by microelectrophoresis conducted on an agarose coated microscope slide. Quantification was performed by measuring the optical density of the metachromatic toluidine blue stained spot an comparing with the standard reference curve of heparin run simultaneously. The results showed that the difference in concentration of heparin in units per gram of wet tissue, was not significant when the "clinically normal" (26 +/- 1.9) was compared with mildly inflamed (24.4 +/- 4.7) gingiva. However, the concentration of heparin in severe gingivitis (79 +/- 7) was significantly higher. Gingival heparin could play important role in the established periodontal lesions, acting as a local factor or co-factor in periodontal bone destruction.
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PMID:Extraction and quantification of heparin in "clinically normal" and inflamed gingiva of the dog. 1188 34

The role of matrix metalloproteinases (MMPs) in response to mechanical forces in orthodontic tooth movement has only been partially clarified. In the present in vivo pilot study, the presence, levels, and degree of activation of MMP-1 and -8 were measured daily for 1 month in gingival crevicular fluid (GCF) of patients treated with orthodontic fixed appliances. GCF samples were collected from five orthodontic patients and three controls from one upper or lower central incisor or from one upper canine before fixed appliance activation and every 24 hours for 1 month thereafter. The molecular forms and activation degrees of MMP-1 and -8 in GCF were analysed by Western blotting, and MMP-8 levels determined by immunofluorometric assay (IFMA).IFMA revealed, during the study period, on average 12-fold higher levels (56 +/- 50 versus 4.6 +/- 4 microg/l) of MMP-8 in orthodontic GCF than in control GCF. The MMP-8 levels in orthodontic GCF were lower than those detected in gingivitis and periodontitis GCF, but significantly higher than in control GCF. IFMA analysis was confirmed by Western blot analysis showing elevated MMP-8 levels from orthodontic GCF relative to control GCF. Forty-one per cent of total MMP-8 immunoreactivities were high-molecular weight complexes (>100 kDa), 32 per cent in the 75 kDa pro-polymorphonuclear (PMN)-MMP-8 form, 14 per cent in the 60 kDa active-PMN-MMP-8 form, and 13 per cent in the 55 kDa fibroblast-type pro-MMP-8 form. In the GCF of orthodontic patients no MMP-1 immunoreactivities were detected. MMP-8 and -1 levels in the control GCF were low and not detectable. These results demonstrate that in vivo in human GCF, elevation and partial activation of multiple species of PMN- and fibroblast-type MMP-8 reflect periodontal remodelling during orthodontic tooth movement.
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PMID:Matrix metalloproteinase-1 and -8 in gingival crevicular fluid during orthodontic tooth movement: a pilot study during 1 month of follow-up after fixed appliance activation. 1581 30

A novel immunology-based point-of-care test has been designed to assess the activated form of matrix metalloproteinase-8 (aMMP-8) for diagnosis and monitoring of periodontal diseases. The test has been automated using an analyzer, which quantitatively measures aMMP-8 in 18 min in gingival crevicular fluid (GCF). Fluid samples were collected from healthy, gingivitis-, and periodontitis-affected teeth. The test results from the analyzer were compared with quantitative aMMP-8 immunofluorometric assay (IFMA) and in-house enzyme-linked immunosorbent assay (ELISA) as well as with the periodontal state. Preliminary results of analyzer measurements of these 34 clinical samples showed a good agreement with the results from IFMA and in-house ELISA and with the clinical picture.
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PMID:Evaluation of immunoassay-based MMP-8 detection in gingival crevicular fluid on a point-of-care platform. 1743 56

Matrix metalloproteinases (MMPs), the key enzymes responsible for matrix degradation, are derived from polymorphonuclear leukocytes during the early stages of periodontitis. The present study determined the levels of GCF matrix metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9) and salivary MMP-8 in patients with gingivitis and periodontitis and in healthy controls. Levels of crevicular MMP-2, MMP-9 and salivary MMP-8 were determined by ELISA in subjects with healthy gingiva (n = 15), gingivitis (n = 18) and periodontitis (n = 20). Significantly higher salivary MMP-8 and crevicular MMP-9 were observed in cases of periodontitis compared to gingivitis and healthy adults. On the other hand, crevicular MMP-2 levels in periodontitis subjects were lower than those in gingivitis and healthy subjects. The three MMP levels were highly correlated to probing depth, and bleeding on probing. Salivary MMP-8, crevicular MMP- 2 and 9 may serve as biomarkers of periodontal disease and aid in early detection of periodontitis or gingivitis.
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PMID:Biomarkers of periodontitis in oral fluids. 1840 84


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