Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 molecular sites of crosslinking between types II and IX collagens of bovine articular cartilage have been defined. All 3 chains of the type IX molecule, alpha 1 (IX), alpha 2 (IX) and alpha 3 (IX), contain an hydroxylysine close to the N-terminus of the central COL2 triple helical domain that can crosslink to an hydroxylysine aldehyde in an alpha 1 (II) N-telopeptide. One chain, alpha 3 (IX), also contains a triple helical hydroxylysine farther into COL2 that crosslinks specifically to an alpha 1 (II)C-telopeptide. The metalloprotease, stromelysin, is capable of depolymerizing the type II-type IX complex by bisecting the type IX collagen molecule and cleaving telopeptides from type II collagen. We discuss the significance of these findings in understanding the structure, growth and remodeling of the heterotypic collagen network of articular cartilage.
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PMID:The cartilage collagens: structural and metabolic studies. 202 30

Enhanced wound healing is elicited by exogenous administration of transforming growth factor- beta 1 (TGF- beta 1) in split-thickness, excisional wounds in the pig (Quaglino, Lab Invest 63:307-319, 1990). A study was designed to investigate if the selective and localized effects of TGF-beta 1 found in the previous model were dependent upon the type of wound or could be considered a more general effect of the cytokine. Transdermal, sutured incisions in the pig were evaluated by conventional histology and by in situ hybridization to reveal locally affected gene expression of collagen, elastin, fibronectin, stromelysin, TGF- beta 1, and basic fibroblast growth factor. Granulation tissue formation was markedly enhanced at 6 d by a single injection of recombinant human TGF beta 1 at the time of wound closure. Although granulation tissue was confined within the margins of the incisional wound, prominent differences in hybridization signals were observed between control and treated wounds. The stimulatory effect of TGF- beta 1 on granulation tissue formation was accompanied by a distinct enhancement in cells expressing mRNA for several different extracellular matrix proteins including collagens type I and III and elastin, whereas a single injection of human recombinant TGF beta 1 (4 micrograms) at the wound site diminished the expression of the neutral metalloprotease, stromelysin, and enhanced the frequency and intensity of cells expressing TGF- beta 1. The data reinforce the concept that TGF- beta 1 can act as a potent, auto-inductive modulator of connective tissue remodeling during the repair process.
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PMID:Transforming growth factor-beta stimulates wound healing and modulates extracellular matrix gene expression in pig skin: incisional wound model. 205 91

Transforming growth factor beta 1 (TGF-beta 1) inhibits the growth factor and oncogene induction of transin/stromelysin, a secreted matrix-degrading metalloprotease. We demonstrate that a 10 bp element in the transin promoter is required for the TGF-beta 1 inhibitory effects and that this sequence is conserved in the promoter regions of several other TGF-beta 1-inhibited genes. The TGF-beta 1 inhibitory element (TIE) specifically binds a nuclear protein complex from TGF-beta 1-stimulated rat fibroblasts. Interestingly, this complex contained the c-fos proto-oncogene product, Fos, and induction of Fos expression was required for the inhibitory effect of TGF-beta 1 on transin gene expression. These results suggest that TGF-beta 1 inhibition of gene expression is mediated by the binding of a Fos-containing protein complex to the TIE promoter sequences.
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PMID:TGF-beta 1 inhibition of transin/stromelysin gene expression is mediated through a Fos binding sequence. 211 31

Stromelysin (transin) is a secreted metalloprotease that is transcriptionally induced by a variety of growth factors and oncogenes. We examined the necessity of specific secondary (protein kinase C) and tertiary (c-fos and c-jun protein products) messengers in the transactivation of stromelysin gene expression by epidermal growth factor (EGF). Rat-1 fibroblasts exposed to antisense c-fos DNA or RNA demonstrated that c-fos expression was necessary for complete EGF induction of stromelysin expression. Similar results demonstrating the necessity of c-jun protein in the EGF induction of stromelysin were obtained. We also demonstrated that protein kinase C activation is required for the EGF induction of stromelysin, since phorbol ester desensitization of C kinase proteins abolished the ability of EGF to induce stromelysin mRNA, protein, and promoter activity. In reconstitution experiments, neither c-fos, c-jun, nor C kinase activation alone induced significant stromelysin expression. Overexpression of c-fos and c-jun was able to induce stromelysin to a level similar to that of the growth factor, and stimulation of protein kinase C activity augmented this induction. The data suggest that the EGF induction of stromelysin in rat fibroblasts procedes through a pathway involving c-fos, c-jun, and protein kinase C.
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PMID:Epidermal growth factor stimulation of stromelysin mRNA in rat fibroblasts requires induction of proto-oncogenes c-fos and c-jun and activation of protein kinase C. 211 24

Extracellular matrix metalloproteases are secreted by the resident cells of the tissue in a proenzyme form, and their extracellular activity is regulated at the level of gene expression, proenzyme activation, and interaction with inhibitors. To understand the molecular mechanisms that control the activity of ECM metalloproteases and their effect on the cellular phenotype, we have established cell lines in which the transcription of the protease genes is repressed. We also have undertaken a detailed study of the pathway of extracellular activation of interstitial procollagenase. Stable transfection of three human tumor cell lines--H-ras-transformed bronchial epithelial cells TBE-1, fibrosarcoma cells HT1080, and melanoma cells A2058--with the adenovirus E1A gene dramatically repressed the expression of the secreted proteases, type IV and interstitial collagenases, and urokinase-type plasminogen activator. Concomitantly, E1A-expressing cells showed reduced metastatic activity in vivo and reduced ability to traverse a reconstituted basement membrane in vitro. Monospecific anti-type IV collagenase antibody inhibited the invasive activity of parental tumor cell lines in the in vitro system, suggesting a possible causal relationship between the effect of E1A on the expression of secreted proteases and the reduced metastatic potential of the E1A-expressing transformants. We have also studied the mechanism of regulation of metalloprotease activity at the level of extracellular activation by investigating the cascade of proteolytic events that results in the activation of interstitial procollagenase. Cocultivation of the major cellular components of skin, dermal fibroblasts, and epidermal keratinocytes induces activation of interstitial procollagenase and prostromelysin in the presence of plasminogen. This activation occurs through a uPA-plasmin-dependent pathway in which plasmin catalyzes the first step in activation of both collagenase and stromelysin by amino-terminal processing. Activated stromelysin can in turn convert plasmin-activated collagenase into a fully active enzyme by removal of approximately 15 amino acid residues from the carboxyl end of the enzyme. This second step of activation results in a 5-8-fold further increase in specific activity of collagenase. This cascade of proteolytic events may constitute a major physiologic pathway of collagenase activation.
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PMID:Secreted proteases. Regulation of their activity and their possible role in metastasis. 215 52

The treatment of HL-60 promyelocytic leukemia cells with phorbol esters (12-O-tetradecanoylphorbol-13-acetate) results in the appearance of cell substrate adhesion and the release of a Mr 94,000 gelatin-degrading metalloprotease. The appearance of the metalloprotease in the culture medium directly correlates with the timing and extent of cell substrate adhesion over a 24-h period. Anti-Mr 94,000 metalloprotease blocking antibodies were unable to interfere with the HL-60 cell substrate adhesion induced by 12-O-tetradecanoylphorbol-13-acetate, although they were able to specifically remove the Mr 94,000 gelatin-degrading activity from either HL-60 or U-937 cell-conditioned medium. A purified metalloprotease preparation was found to be predominantly latent and activated by organomercurials, acid treatment (pH 2 to 3.6), or 8 M urea. The activating effect of the latter two denaturing treatments suggests that conformational changes may be the common activating mechanism. The different treatments also caused the appearance of lower molecular weight gelatin-degrading bands (in gelatin zymogram gels) in a manner consistent with the autocatalytic cleavage that occurs with other collagnase proenzymes during activation. Edman degradation of a cyanogen bromide fragment from the Mr 94,000 metalloprotease provided the amino acid sequence [PR(C)GVPD] which is present in type I collagenase, stromelysin, and transin proenzyme sequences and partially conserved (V----N substitution) in the type IV collagenase proenzyme. This sequence has been reported to be important in the maintenance of the latent state of the transin proenzyme (R. Sanchez-Lopez et al., J. Biol. Chem., 263: 1892-11899, 1988) and is a sequence unique to collagenase proenzymes. The N-terminal sequence of the Mr 94,000 metalloprotease (AP-QDQST) is unique and distinct from other collagenases. Thus, the Mr 94,000 metalloprotease from HL-60 cells appears to be a distinct and new member of the collagenase family of proteases.
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PMID:A latent Mr 94,000 gelatin-degrading metalloprotease induced during differentiation of HL-60 promyelocytic leukemia cells: a member of the collagenase family of enzymes. 229 60

The activity of stromelysin and collagenase was determined in fibrillated human OA cartilage using labeled proteoglycans and type II collagen as substrates. In vitro paracetamol had no effect on metalloprotease whereas TA induced a significant inhibition of stromelysin. In cartilage and synovium from nine patients treated with TA and nine patients treated with paracetamol during 8 weeks before surgery for hip OA, stromelysin activity was significantly lower in the TA than in the paracetamol group. The results suggest that TA has a potential chondroprotective effect in OA.
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PMID:Cartilage degradative enzymes in human osteoarthritis: effect of a nonsteroidal antiinflammatory drug administered orally. 231 5

Tendon repair following trauma, rupture, or surgery involves both synthesis and degradation of collagen in order to reweave new collagen bundles in with the old. Using an in situ assay on polyacrylamide gels containing gelatin, we have identified protease activity from tendon tissue and from tendon cells in culture. A population of synovial cells from the epitenon surrounding the tendon as well as the tendon fibroblasts themselves were examined. The cells and the conditioned medium from both cell populations exhibited a major band of gelatin-degrading activity at 70 kdaltons and a minor band of activity at 60 kdaltons. When preparations were reacted with p-aminophenylmercuric acetate (APMA) before electrophoresis, a third band appeared at 63 kdaltons. The main band at 70 kdaltons comigrated with a [35S]methionine-radiolabeled protein band. Inhibitor and pH studies identified the enzymes as neutral metalloproteases requiring disulfide bonds for activity. No proteolytic activity was detected on casein-containing gels, ruling out the presence of stromelysin. Since electrophoresis in the presence of SDS would separate the metalloprotease from the smaller molecular weight inhibitor (TIMP), these in situ assays provide a sensitive screening system for gelatin-degrading enzymes present in tendon without prior removal of TIMP.
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PMID:Neutral metalloprotease from tendons. 253 97

Various proteases have been found to be released by the growth cones of developing neurons in culture and have been hypothesized to play a role in the process of axon elongation. We report here that nerve growth factor (NGF) induced the gene encoding the metalloprotease transin in PC12 cells with a time course coincident with the initial appearance of neurites by these cells. Acidic and basic fibroblast growth factors also stimulated transin mRNA expression and neurite outgrowth, whereas various other agents had no effects on either of these phenomena. In contrast, dexamethasone was found to inhibit the induction of transin mRNA when added with, or following, NGF treatment. Finally, we show that sequences contained within 750 bp of the 5' untranscribed region of the transin gene confer responsiveness to NGF and dexamethasone.
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PMID:NGF induction of the gene encoding the protease transin accompanies neuronal differentiation in PC12 cells. 256 Jun 48


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