Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 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

Extracellular matrix (ECM) plays an important role in the maintenance of mammary epithelial differentiation in culture. We asked whether changes in mouse mammary specific function in vivo correlate with changes in the ECM. We showed, using expression of beta-casein as a marker, that the temporal expression of ECM-degrading proteinases and their inhibitors during lactation and involution are inversely related to functional differentiation. After a lactation period of 9 d, mammary epithelial cells maintained beta-casein expression up to 5 d of involution. Two metalloproteinases, 72-kD gelatinase (and its 62-kD active form), and stromelysin, and a serine proteinase tissue plasminogen activator were detected by day four of involution, and maintained expression until at least day 10. The expression of their inhibitors, the tissue inhibitor of metalloproteinases (TIMP) and plasminogen activator inhibitor-1, preceded the onset of ECM-degrading proteinase expression and was detected by day two of involution, and showed a sharp peak of expression centered on days 4-6 of involution. When involution was accelerated by decreasing lactation to 2 d, there was an accelerated loss of beta-casein expression evident by day four and a shift in expression of ECM-remodeling proteinases and inhibitors to a focus at 2-4 d of involution. To further extend the correlation between mammary-specific function and ECM remodeling we initiated involution by sealing just one gland in an otherwise hormonally sufficient lactating animal. Alveoli in the sealed gland contained casein for at least 7 d after sealing, and closely resembled those in a lactating gland. The relative expression of TIMP in the sealed gland increased, whereas the expression of stromelysin was much lower than that of a hormone-depleted involuting gland, indicating that the higher the ratio of TIMP to ECM-degrading proteinases the slower the process of involution. To test directly the functional role of ECM-degrading proteinases in the loss of tissue-specific function we artificially perturbed the ECM-degrading proteinase-inhibitor ratio in a normally involuting gland by maintaining high concentrations of TIMP protein with the use of surgically implanted slow-release pellets. In a concentration-dependent fashion, involuting mammary glands that received TIMP implants maintained high levels of casein and delayed alveolar regression. These data suggest that the balance of ECM-degrading proteinases and their inhibitors regulates the organization of the basement membrane and the tissue-specific function of the mammary gland.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Coordinated expression of extracellular matrix-degrading proteinases and their inhibitors regulates mammary epithelial function during involution. 151 97

Degradation of cartilage matrix macromolecules depends on the increase of metalloprotease activity. It has been suggested that interleukin 1 (IL-1) contributes to cartilage break-down by modulating the synthesis of the elements favoring an activation of these metalloenzymes. We analyzed the effect of IL-1 on the synthesis of collagenase, stromelysin, and tissue inhibitor of metalloproteases (TIMP) in human cartilage explants and culture chondrocytes, as well as its effect on the secretion of plasminogen activators (t-PA, u-PA) and inhibitors (PAI-1, PAI-2) in cartilage explants. Messenger RNA levels of collagenase and TIMP were also analyzed following chondrocyte incubation in the presence or absence of IL-1. We demonstrate that IL-1 stimulates the secretion of metalloproteases and t-PA in a dose dependent manner. At a relatively low concentration (5 pg/ml), IL-1 induced collagenase and stromelysin synthesis in parallel with a decline in TIMP secretion. While IL-1 induced collagenase gene expression, no change in the TIMP mRNA level was noted. The increase in t-PA synthesis was accompanied by a decreased PAI-1 level, while the PAI-2 level remained unchanged. u-PA could not be detected in the culture medium. This study gives insight into the ways that the synthesis, activation and inhibition of metalloproteases are modulated by IL-1. These results support the importance of IL-1 in the etiology of cartilage degeneration.
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PMID:In vitro effects of interleukin 1 on the synthesis of metalloproteases, TIMP, plasminogen activators and inhibitors in human articular cartilage. 185 Dec 31

The paper deals with a potential role of fibronectin proteolysis associated with plasma cell membrane receptors in the control of cell behaviour. The molecule of fibronectin contains at least 5 adhesive domains providing its interaction with cell receptors and at least 2 domains interacting with other molecules of an extracellular matrix (ECM). Different cells in various states (steady state, motion, proliferation) interact with all or some of the adhesive domains of fibronectin. Limited fibronectin proteolysis as a linking between the cell and ECM results in a change in the cell status. Limited proteolysis of cell-bound fibronectin may occur with several proteinases: 1) uPA having a receptor in the focal contact of a cell; 2) plasmin resulted from plasminogen under the action of uPA; 3) stromelysin whose synthesis is induced by fibronectin proteolytic fragments; 4) metalloproteinases secreted by some cells and involving in the hapatotactic motion of a cell over fibronectin. Proteolysis of fibronectin and other ECM molecules may be inhibited itself due to proteolysis-induced release of inhibitors via binding to fibronectin (proteasonexin) and via binding to other ECM molecules (PAI-1). The fact that there is a direct and inverse correlation in the proteolytic process associated with a fibronectin cell (and other ECM molecules) indicate that the behavior of a cell can be controlled by the mechanism of proteolytic impairment of the cell-EMC and cell-cell bonds.
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PMID:[The role of fibronectin and possible participation of its proteolytic fragments in the changes in cell behavior]. 204 46

To understand the mechanisms regulating osteoid removal by osteoblasts, mouse calvarial osteoblasts were grown on 14C-labelled type I collagen films and stimulated with 1,25-dihydroxyvitamin D-3 (2.5.10(-8) M) for 48-72 h. In the presence of 5% non-inhibitory rabbit serum this resulted in a 2-3-fold increase in collagen degradation and a dramatic change in osteoblast morphology, when compared with untreated osteoblasts. Collagenolysis was accompanied by increased synthesis and release of latent collagenase, gelatinase and stromelysin and a concomitant decrease in their specific inhibitor, TIMP (tissue inhibitor of metalloproteinases). In serum-free medium, osteoblasts failed to degrade collagen, but their ability to lyse collagen could be restored by adding plasminogen (5 micrograms/ml) to the cultures. Plasminogen-dependent collagenolysis was inhibited by human recombinant TIMP (5 units/ml), demonstrating that plasmin, derived from plasminogen, activated latent collagenase and did not itself degrade collagen. Plasminogen activator production was confirmed by culturing osteoblasts on 125I-labelled fibrin plates. Comparison with urokinase-type and tissue-type plasminogen activator standards suggested that osteoblast plasminogen activator was predominantly cell-associated and likely to be of the urokinase type. Immunocytochemistry indicated that osteoblasts also constitutively produce plasminogen activator inhibitor-1. These findings provide evidence for the involvement of a plasminogen-plasmin-latent metalloproteinase activation cascade in type I collagen degradation by osteoblasts, and for its regulation by TIMP and plasminogen activator inhibitor-1.
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PMID:Type I collagen degradation by mouse calvarial osteoblasts stimulated with 1,25-dihydroxyvitamin D-3: evidence for a plasminogen-plasmin-metalloproteinase activation cascade. 255 72

Plasmin-mediated extracellular proteolysis has been implicated in the degradation of bone in normal and pathological conditions. Normal and malignant osteoblasts can produce both tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). We have used the osteosarcoma cell line MG63 to address the question of whether the enhanced bone turnover in osteosarcomas is mediated by t-PA or by u-PAA and to study the effect of the cytokine interleukin-1 alpha (IL-1 alpha), known to influence bone degradation, on the plasminogen activator production and extracellular matrix degradation in malignant osteoblastic cells. Furthermore, the effect of IL-1 alpha on the synthesis of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) was analyzed. u-PA production by MG63 was high (approximately 180 ng/10(6) cells/24 h). Also t-PA and PAI-1 production was observed. u-PA production was rapidly increased in MG63 by IL-1 alpha (10 ng/ml), whereas an effect on t-PA production was only found after a prolonged incubation and hardly any effect of IL-1 alpha on PAI-1 production was observed. mRNA analysis revealed similar effects. u-PA receptor (u-PAR) mRNA was detectable in MG63 cells and could be increased by IL-1 alpha after 24 h. In MG63, u-PA-mediated extracellular matrix degradation was detectable, and IL-1 alpha increased the u-PA-mediated matrix degradation (approximately 2-fold). Under control conditions in MG63, only MMP-2, TIMP-1, and TIMP-2 mRNA could be observed. After the addition of IL-1 alpha, a very rapid increase in MMP-1 and MMP-3 mRNA could be observed as well as a moderate increase in TIMP-1 mRNA. The presence of MMP-2 was demonstrated by gelatin zymography. These results show that IL-1 alpha can stimulate u-PA production and can regulate extracellular proteolytic activity mainly via u-PA induction in the MG63 osteosarcoma cell line. Furthermore, IL-1 alpha has a strong stimulating effect on the production of MMP-1 and MMP-3. These findings suggest that u-PA and possibly MMP-1 and MMP-3 play an important role in the process of bone turnover in osteosarcomas.
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PMID:Regulation of plasminogen activation, matrix metalloproteinases and urokinase-type plasminogen activator-mediated extracellular matrix degradation in human osteosarcoma cell line MG63 by interleukin-1 alpha. 750 10

Endothelial cell-derived proteases can be classified according to their physiological role. The proteases involved in extracellular matrix degradation are important in endothelial cell migration and thereby in angiogenesis. They include the urokinase-type plasminogen activator (uPA) and the metalloproteases, collagenases, gelatinases and stromelysin. uPA secreted from endothelial cells remains associated with the cell membrane, on specific receptors localized in the vicinity of the receptors for plasminogen. This favours the local activation of plasminogen into plasmin. Plasmin, generated on the cell surface, is fully active as it is not inhibited by alpha 2-antiplasmin. Plasmin acts directly by degrading some components of the extracellular matrix and indirectly by activating the prometalloproteases. Secretion of PAI by migrating cells is generally stimulated by the same factors that induce uPA secretion, limiting the degradation of the matrix to the pericellular path. The degradation of the fibrin clot involves the tissue-type plasminogen activator tPA, which like the uPA activates plasminogen to plasmin. This system is also regulated by two different mechanisms. On the one hand, fibrin itself favours its own degradation by formation of a ternary complex, fibrin-plasminogen-tPA, in which the affinity of tPA for plasminogen is markedly increased, as compared to the affinity of unbound tPA. In addition, plasmin generated on the clot is protected from inhibition by alpha 2-antiplasmin. On the other hand, as for uPA, tPA is inhibited by PAI-1. The importance of the regulation of this system is illustrated by the thrombotic risk observed when there is either a decrease in tPA or an increase in PAI-1, and inversely by haemorrhages in the case of increase in tPA.
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PMID:Endothelial cell proteases: physiological role and regulation. 751 36

Plasmin and matrix metalloproteinases (MMPs) both participate in extracellular matrix remodeling. This study examined the effects of tumor necrosis factor-alpha (TNF-alpha) and plasminogen on collagenase, stromelysin, and plasminogen activator inhibitor-1 (PAI-1) synthesis of collagenase and stromelysin, which remained predominantly in proenzyme forms, as determined by Western analysis of culture media. In contrast, plasminogen and plasmin not only increased secretion of MMPs but also induced cleavage to their active forms. The serine protease inhibitor aprotinin inhibited this activation of MMPs by plasminogen and plasmin. TNF-alpha reduced plasminogen-induced activation of MMPs, suggesting induction of an inhibitor or plasmin generation, such as PAI-1. Enzyme-linked immunosorbent assay of culture media showed that TNF-alpha (10 ng/mL) increased PAI-1 secretion by 4.2 fold compared with control (105.5 +/- 9.6) versus 24.9 +/- 1.7 ng/mL, n = 3). Surprisingly plasminogen also increased PAI-1 secretion by vascular SMCs (3.6-fold over control). These results demonstrate coordination of cytokines and serine proteases in regulating MMP secretion and activation. In addition, the induction of PAI-1 by TNF-alpha and plasminogen suggests a negative feedback mechanisms limit both plasmin-mediated and MMP-mediated matrix degradation.
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PMID:Regulation of matrix metalloproteinases and plasminogen activator inhibitor-1 synthesis by plasminogen in cultured human vascular smooth muscle cells. 860 4

The studies described here examine the involvement of the fibrinolytic cascade and its endogenous inhibitors in the regulation of activity of matrix metalloproteinases and cartilage degradation related to non-inflammatory joint disease, like osteoarthritis. An interleukin-1-induced model of degradation using [35S]-labeled bovine and human articular cartilage explants was utilized. One goal of these studies was to compare the responses of bovine and human articular cartilage. Degradation was not inhibited by alpha 1-PI, PAI-1, alpha 2-macroglobulin, alpha 2-antiplasmin or TIMP-2, when IL-1 alone was added. Addition of human plasminogen to bovine explants, at concentrations found in human synovial fluid, increased degradation by three to four-fold. Under these conditions, the degradation was inhibited effectively by all of the endogenous inhibitors tested, indicating the presence of a cascade where activated chondrocytes are a source of u-PA. Plasminogen activated by u-PA gives plasmin, which is known to further activate pro-stromelysin. Stromelysin is essential for activation of collegenase. Not only TIMP, but also inhibitors at earlier steps of activation like PAI-1, alpha 2-antiplasmin, alpha 1-PI and alpha 2-macroglobulin inhibited degradation, and could provide cartilage protection in vivo. An experiment with human articular cartilage explants showed that very little or no degradation occurred when human articular cartilage explants were stimulated with interleukin-1 alone. Addition of human plasminogen (at physiologically relevant concentrations) resulted in significant degradation, which was inhibited in the same manner as in bovine explants, by inhibitors of the fibrinolytic cascade and TIMP. TIMP is much more efficient in human explants, indicating the limited participation of human plasmin in the degradation of human cartilage. Although speculative, it is possible that in vivo, cartilage degradation could be promoted not only by TIMP/MMP imbalance, but also accelerated by decreased levels of certain serpins in synovial fluid (e.g. PAIs, alpha 2-antiplasmin and alpha 1-PI).
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PMID:Plasminogen modulation of IL-1-stimulated degradation in bovine and human articular cartilage explants. The role of the endogenous inhibitors: PAI-1, alpha 2-antiplasmin, alpha 1-PI, alpha 2-macroglobulin and TIMP. 889 58

Al-trans retinoic acid (RA) enhanced human, S-type, SK-N-SH neuroblastoma cell invasion of reconstituted basement membrane in vitro but did not induce terminal differentiation of this cell line. In contrast to basal invasion, which was urokinase (uPA)- and plasmin-dependent, RA-enhanced invasion was dependent on tissue-type plasminogen activator (t-PA) and plasmin activity. Neither basal nor RA-enhanced invasion involved TIMP-2 inhibitable metalloproteinases. Enhanced invasion was associated with the induction of t-PA expression, increased expression of the putative t-PA receptor amphoterin, increased association of t-PA with cell membranes and increased net membrane-associated PA activity. Enhanced invasion was not associated with significant changes in the expression of uPA or its membrane receptor UPAR; plasminogen activator inhibitors PAI-1 and PAI-2; metalloproteinases MMP-1, MMP-2, MMP-3, MMP-9 and membrane type MMP1; or tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2. RA stimulated the association of t-PA with the external cell membrane surface, which could be inhibited by heparin sulphate but not by mannose sugars or chelators of divalent cations, consistent with a role for amphoterin. Our data indicate that RA can promote the malignant behavior of S-type neuroblastoma cells refractory to RA-mediated terminal differentiation by enhancing their basement membrane invasive capacity. We suggest that this results from the action of a novel, RA-regulated mechanism involving stimulation of t-PA expression and its association with the cell membrane leading to increased PA-dependent matrix degradation.
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PMID:Retinoic acid-enhanced invasion through reconstituted basement membrane by human SK-N-SH neuroblastoma cells involves membrane-associated tissue-type plasminogen activator. 939 56


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