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)

Inflammation of the periodontium leads to connective tissue degradation and eventual tooth loss. The regulation of matrix metalloproteinases (MMPs) has been studied to determine their role in these processes and also during tissue remodelling. Analysis of gingival crevicular fluid has revealed the presence of collagenase and gelatinase that, in the acute stages of periodontal disease, are derived predominantly from polymorphonuclear leukocytes. These MMPs appear to be intimately associated with tissue destruction since the levels of the active forms of these enzymes obtained from either crevicular fluid or mouthrinse samples correlate with tissue destruction and, therefore, provide a sensitive means of demonstrating disease activity. Transforming growth factor-beta, an important regulator of connective tissue remodelling, has been implicated in the rapid remodelling of periodontal tissues. TGF-beta promotes tissue matrix formation by stimulating both the synthesis of matrix proteins (collagen, fibronectin and SPARC) and proteinase inhibitors (TIMP, PAI-1) and by decreasing the synthesis of MMPs, but not the 72 kDa-gelatinase. Nuclear run-on analyses have shown that TGF-beta reduces collagenase and stromelysin synthesis by suppressing gene transcription without altering mRNA stabilities. In contrast, the transcription of the gelatinase and TIMP genes was increased by TGF-beta, which also increased gelatinase mRNA stability. Remodelling of alveolar bone involves interaction between osteoblasts and osteoclasts. Osteoblasts, under the influence of osteotropic hormones (vit D3, PTH and retinoic acid), produce MMPs which appear to function in the removal of soft tissue that precludes access of osteoclasts to the mineralized tissue surface. Rat osteoblastic cells produce MMPs with activity on native collagen, native collagen 3/4-fragments and gelatin and, in addition, two forms of TIMP activity. The 3/4-collagen endopeptidase, purified to apparent homogeneity, also has significant collagenase and gelatinase activities and an amino terminal sequence almost identical to human 72 kDa-gelatinase. The production of this enzyme was stimulated by TGF-beta, which suppresses bone resorption, and by osteotropic hormones which stimulate bone resorption, supporting a bifunctional role for the gelatinase in connective tissue remodelling. Although there is strong evidence for the involvement of MMPs in the resorption of bone and in the inflammation-mediated destruction of periodontal tissues, the role of MMPs in the remodelling of mature soft connective tissues remains equivocal.
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PMID:Matrix metalloproteinases in periodontal tissue remodelling. 148 60

Stromelysin/Transin is a member of the matrix metalloprotease gene family. This metalloprotease is synthesized as a preproenzyme with a predicted size of 53,977 Da including a 17 amino acid signal peptide. Prostromelysin is secreted from normal and transformed cells in two forms with apparent molecular masses on NaDodSO4 gels of 60 and 58-kDa. The minor 60-kDa species contains N-linked oligosaccharide(s). Stromelysin consists of three domains the amino terminal propeptide(s) domain contains the tribasic amino acid sequence RRK which is important in the proteolytic activation of this zymogen by trypsin-like serine proteases. The second domain consists of the catalytic domain which contains the zinc binding site. The carboxyl-terminal hemopexin domain has no known function and can be removed without a loss of enzymatic activity. Stromelysin has a broad range of substrate specificity including proteoglycans, casein, fibronectin, laminin, native type IV and IX collagen and gelatin but not type I collagen. In the presence of trypsin or plasmin, catalytic amounts of this enzyme can also fully activate interstitial fibroblast collagenase. We have developed a panel of monoclonal antibodies against stromelysin which will be useful for the tissue localization of the various species of this enzyme in tissues. In addition, we have demonstrated that either human rIL-1 (alpha) or rTNF (alpha) can stimulate the expression of this enzyme in cultured bovine articular cartilage at least 10-fold. Based on western blot analysis, the zymogen form of the enzyme was the major enzyme species detected in either the media or cartilage matrix compartments of cytokine treated cultures.
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PMID:Primary structure and function of stromelysin/transin in cartilage matrix turnover. 148 63

The anabolic steroid, stanozolol, is used therapeutically to treat a number of pathological conditions and its clinical effects suggest that it can modulate connective tissue breakdown. The ability of this compound to stimulate prostaglandin E2 (PGE2), collagenase, gelatinase and stromelysin production by human synovial and skin fibroblasts in vitro was examined. The results showed that stanozolol significantly stimulated, in a dose dependent manner, PGE2, collagenase and stromelysin production by skin fibroblasts. However, no stimulation was seen in the synovial cell lines. In contrast, no effect on gelatinase production was seen in either cell type, following exposure to stanozolol. The synovial and skin lines both exhibited a significant stimulation of PGE2 and all three metalloproteinases in response to interleukin-1 beta (IL-1 beta). The anabolic steroids nortestosterone and oxymetholone demonstrated no ability to stimulate PGE2 or collagenase production in either skin or synovial fibroblasts. These results suggest that stanozolol exerts differential effects on skin and synovial fibroblasts in vitro which may enable the elucidation of the mechanism of action of the compound in vivo.
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PMID:The differential responses of human skin and synovial fibroblasts to stanozolol in vitro: production of prostaglandin E2 and matrix metalloproteinases. 152 98

(7-methoxycoumarin-4-yl)Acetyl-Pro-Leu-Gly-Leu-(3-[2,4-dinitrophenyl]-L- 2,3-diaminopropionyl)-Ala-Arg-NH2 (Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2) has been synthesised as a fluorogenic substrate for the matrix metalloproteinases. The highly fluorescent 7-methoxycoumarin group is efficiently quenched by energy transfer to the 2,4-dinitrophenyl group. The punctuated metalloproteinase (PUMP, EC 3.4.24.23) cleaves the substrate at the Gly-Leu bond with a 190-fold increase in fluorescence (lambda cx 328 nm, lambda cm 393 nm). In assays of the human matrix metalloproteinases. Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 is about 50 to 100 times more sensitive than dinitrophenyl-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH2 and continuous assays can be made at enzyme concentrations comparable to those used with macromolecular substrates. Specificity constants (kcat/Km) are reported for both synthetic substrates with PUMP, collagenase, stromelysin and 72 kDa gelatinase.
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PMID:A novel coumarin-labelled peptide for sensitive continuous assays of the matrix metalloproteinases. 153

Tooth eruption is defined as the movement of a tooth from its site of development within the jaws to its position of function within the oral cavity. We present a critical review of evidence for the mechanisms and regulation of the intraosseous and supraosseous phases of eruption, with an emphasis upon the canine premolar model studied by the authors. Analyses at different stages of premolar eruption indicate that selective fragmentation of dental follicle protein DF-95 correlates with the presence of elevated levels of follicular collagenase and stromelysin, and with the onset of premolar movement. A dramatic decrease in these metalloproteinases followed initiation of movement. A biochemical and cell biological model for regulation of tooth eruption is proposed based upon these new and existing data.
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PMID:Current concepts of the biology of tooth eruption. 157 71

Normal and osteoarthritic (OA) human articular cartilage chondrocytes, released enzymatically in the presence of 0.5% fetal calf serum, display constitutive expression of early response activating protein (AP-1) genes; c-fos, c-jun and jun-B. Among the late AP-1 responsive genes, total metallothionein (MT) and stromelysin mRNAs were expressed at high levels in both normal and OA chondrocytes, while collagenase and hMT-IIA mRNA levels were elevated only in OA individuals. Despite the common AP-1 sequences present in their promoter regions, the three late genes were differentially expressed.
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PMID:Expression of c-fos, c-jun, jun-B, metallothionein and metalloproteinase genes in human chondrocyte. 163 72

Investigations of the effect of epidermal growth factor (EGF) on the expression of four genes involved in the turnover of the extracellular matrix, collagen type I, collagenase, stromelysin and tissue inhibitor of metalloproteinases (TIMP) were performed on four strains of skin fibroblasts in vitro. Addition of EGF to subconfluent cultures for increasing periods of time up to 5 days induced an inhibition of procollagen alpha 1(I) mRNA and a strong stimulation of collagenase (100-fold) and stromelysin (1000-fold) mRNAs, whereas the mRNA of TIMP was increased to a lesser extent (5-fold). After a 40 h pulse with EGF, these effects persisted for 24-48 h after withdrawal of the growth factor and slowly diminished thereafter to attain control values after several days. By culturing fibroblasts for increasing periods of time, different levels of confluence were obtained allowing for the deposition of an extracellular biomatrix. The steady-state level of collagenase and stromelysin mRNAs were profoundly depressed in confluent as against non-confluent cultures, whereas no major change for TIMP and procollagen alpha 1(I) mRNAs was observed. Upon treatment of these cultures with EGF for 48h, the steady-state level of collagenase, stromelysin and TIMP increased, whereas procollagen alpha 1(I) mRNA was slightly reduced. These modifications were, at least in part, dependent upon a regulation of the transcription rate, as suggested from run-off experiments. Similar states of confluence were obtained by seeding cells at increasing densities in short-term cultures in which cell-cell contact predominated. In such culture conditions, the collagenase and stromelysin mRNAs were enhanced in high as compared to low density cultures. The response to EGF was progressively decreased for collagenase, stromelysin and, to a lesser extent, TIMP mRNAs at most densities and a complete lack of response to EGF at the highest cell density was observed. Under all culture conditions the modulation of collagenase mRNA was paralleled by similar modifications of enzyme activity. These results emphasize the importance of the cell-cell contacts and cell-matrix interactions in the expression of the genes coding for metalloproteinases or their inhibitor and their modulation by growth factors.
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PMID:Effect of cell-cell and cell-matrix interactions on the response of fibroblasts to epidermal growth factor in vitro. Expression of collagen type I, collagenase, stromelysin and tissue inhibitor of metalloproteinases. 163 2

Stromelysin gene expression is transcriptionally activated by a number of growth factors (e.g., EGF and PDGF), tumor promoters (e.g., TPA), and oncogenes (e.g., ras, src) through an AP-1-dependent mechanism. TGF-beta repression of stromelysin induction is mediated at the level of transcription by an element located at position -709 in the rat stromelysin promoter referred to as the TGF-beta inhibitory element (TIE). A TIE-binding protein complex is induced by treatment of rat fibroblasts with TGF-beta. This protein complex contains the protooncogene c-fos, and induction of c-fos by TGF-beta is required for the repressive effects of TGF-beta on stromelysin gene expression. Interestingly, c-fos induction is also required for stimulation of stromelysin expression by EGF in rat fibroblasts. Preliminary studies suggest that differential regulation of members of the jun family of early-response genes may explain this apparent paradox and determine whether stromelysin is induced or repressed by growth factors. TGF-beta stimulation therefore initiates a cascade of events that results in a specific pattern of gene expression: the direct stimulation of early-response genes can lead to subsequent induction or repression of other genes. Growth factor regulation of matrix metalloproteinases appears to play a role in embryonic development in the morphogenesis of the murine lung. Treatment of embryonic lungs in organ culture with the growth factors EGF or TGF-alpha results in stimulation of growth and inhibition of branching morphogenesis. A similar inhibition of branching was observed when these lung rudiments were treated with the matrix metalloproteinase collagenase. Most interestingly, the effects of EGF and TGF-alpha can be completely reversed by the tissue inhibitor of metalloproteinases, TIMP. TGF-beta has the opposite effect on growth of murine lung rudiments--growth is inhibited in a dose-dependent manner. This example illustrates a potential role for growth factor regulation of matrix-degrading metalloproteinases in complex developmental processes.
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PMID:Negative regulation of gene expression by TGF-beta. 163 49

The extracellular matrix (ECM) of articular cartilage is subject to a steady remodelling process. The collagenous components of the ECM are characterized by a very low rate of metabolism, whereas the proteoglycans exhibit an active turnover. The main proteolytic enzymes degrading the ECM components are collagenase, gelatinase and stromelysin. These enzymes undergo under pathological circumstances a remarkable enhancement of synthesis and activity. Although each of these enzymes appears to degrade one ECM component specifically, there is evidence for synergistic effects of most of them. Gelatinase acts synergistically with collagenase in degrading insoluble interstitial collagens and stromelysin activates collagenase. Thus a cascade mechanism may exist in which the cartilage-ECM is completely degraded. Yet, it is not crucial which part of the ECM (collagens or proteoglycans) is primarily degraded. The integrity of the ECM rather depends on the balance between anabolic and catabolic processes, the upset of which results in damage of the articular cartilage. Cartilage destruction in rheumatoid arthritis and osteoarthritis is considered to be a result of this imbalance in favour of the catabolic processes. This would lead to a decrease in proteoglycans which causes fibronectin deposition in the cartilage ECM. Due to chemotaxic effects of fibronectin on fibroblasts, the enrichment of this glycoprotein in the ECM gives rise to cartilage fibrosis and early degeneration.
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PMID:[Proteolytic enzymes and the destruction of articular cartilage in arthritis and chronic polyarthritis]. 164 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


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