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)

Degradative enzyme (proteoglycanase and collagenase) as well as proteoglycan synthesis enzyme (glycosyl-transferase) activity was studied in osteoarthritic fibrillated cartilage. Proteoglycanase activity was significantly lower in 10 patients with hip osteoarthritis treated with Naproxen (1 g/daily for 4 weeks) than in 10 patients treated with acetaminophen. Synthesis enzyme activity was similar in both groups. The results which confirm in vitro studies suggest that naproxen has not toxic effect on human osteoarthritic cartilage and could rather be beneficial.
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PMID:[Effects of naproxen (naprosyne) on the metabolism of arthrotic cartilage in man in vivo]. 205 6

Concentrations of prostaglandin E2, interleukin 1 beta, interleukin 6 and tumor necrosis factor alpha, phospholipase A2, collagenase and proteoglycanase activity were determined in synovial fluid from 26 patients with osteoarthrosis of the knee and 10 with rheumatoid arthritis. Osteoarthrosis synovial fluid was characterised by the absence of interleukin 1 beta while tumour necrosis factor alpha and interleukin 6 were present in relatively large amounts, by a very high phospholipase A2 activity contrasting with a very low concentration of prostaglandin E2, and by a collagenase/proteoglycanase activity only slightly less constant and high as in rheumatoid arthritis. In osteoarthrosis patients, the interleukin 6 concentration, but not that of tumor necrosis factor alpha, was correlated with the collagenase and proteoglycanase activity of synovial fluid.
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PMID:[Cytokines, prostaglandin E2, phospholipase A and metalloproteases in synovial fluid in osteoarthritis]. 205 24

The differentiation of F9 and PSA-1 embryonal carcinoma cells to embryoid bodies composed of a mixture of parietal and visceral endoderm was accompanied by changes in their secretion of metalloproteinases. Differentiation was induced by retinoic acid and dibutyryl cyclic AMP (for F9 cells) or by removing cells from a substrate of feeder cells to alter cell-cell interaction and adhesion (for PSA-1 cells). The embryoid bodies attached to gelatin-coated dishes, and the parietal endoderm cells spread out over the matrix. The differentiated cells secreted specific gelatin- and casein-degrading proteinases, including enzymes that comigrated with proenzyme forms of collagenase and stromelysin. Total proteinase activity as well as specific collagenase activity increased with the time of differentiation. All of the gelatin- and casein-degrading proteinases detectable by substrate gel zymography were inhibited by inhibitors of metalloproteinases but not by inhibitors of serine or cysteine proteinases, indicating that they were metalloproteinases. Both cell lines showed increased collagenolytic activity, which was activated by treatment with plasmin. In addition, both cell lines showed increased secretion of specific metalloproteinase inhibitors, including tissue inhibitor of metalloproteinases, with differentiation. Analysis of mRNA from undifferentiated and differentiated F9 cells by RNA blot analysis or reverse transcription coupled with the polymerase chain reaction showed that increased expression of genes for collagenase, stromelysin and tissue inhibitor of metalloproteinases is associated with differentiation of these cells. These results suggest that the expression of extracellular matrix-degrading metalloproteinases and their inhibitors is developmentally regulated during the differentiation and spreading of the parietal endoderm.
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PMID:Expression of extracellular matrix-degrading metalloproteinases and metalloproteinase inhibitors is developmentally regulated during endoderm differentiation of embryonal carcinoma cells. 208 60

Articular cartilage from arthritic joints of rats immunized with type II collagen is severely depleted of proteoglycans. Depletion begins within 48 hours after the onset of inflammation, prior to extensive pannus formation, and may represent a critical first step in cartilage destruction. We have immunolocalized stromelysin, an enzyme that is believed to play a major role in the pathologic degradation of proteoglycans, in the joints of rats with collagen-induced arthritis. Immunoperoxidase staining of frozen tissue sections demonstrated the presence of stromelysin in both the synovium and chondrocytes. In contrast, collagenase was localized primarily to the pannus-cartilage junction. Neither enzyme was detectable in joints from normal animals. To test the hypothesis that chondrocytes respond directly to inflammatory mediators by increasing the production of stromelysin, isolated chrondrocytes were incubated with various concentrations of interleukin-1. The culture media were also assayed for the presence of stromelysin by immunoreactivity on Western blots and by analysis of enzymatic activity on casein substrate gels. A 3-fold increase in a doublet of proteins synthesized in response to 10 units/ml of interleukin-1 was observed. These proteins also immunoreacted with the stromelysin antibody and degraded casein. Northern blotting results established that the increased levels of stromelysin were accompanied by increases in stromelysin-specific messenger RNA levels. These results suggest that stromelysin is responsible for proteoglycan degradation in early inflammatory arthritis, and that chondrocytes may play a direct role in the earliest stages of the degradation of their own matrices.
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PMID:The role of stromelysin in the cartilage destruction that accompanies inflammatory arthritis. 215 11

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

Molecular cloning has revealed that erythroid potentiating activity (EPA) and tissue inhibitor of metalloproteinases (TIMP) represent two distinct activities of a single protein. We have studied the expression of the EPA/TIMP gene at the mRNA and protein levels during 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced megakaryoblastic differentiation of K562 human chronic myeloid leukemia cells. Northern hybridization analysis showed that the EPA/TIMP mRNA was increased within 3 hours of TPA-induction and reached maximal levels (about 50-fold induction) during the first day of treatment. The expression of mRNAs for two major metalloproteinases, collagenase-I and stromelysin, were activated in parallel in the differentiation-induced K562 cells. The increase of EPA/TIMP mRNA correlated with increased EPA/TIMP protein biosynthesis and secretion: the TPA-induced cells secreted substantially enhanced amounts of metabolically labeled proteins, of which EPA/TIMP represented up to 50% after the first day of treatment (over 100-fold induction). The induction of EPA/TIMP mRNA was associated with its increased transcription. EPA/TIMP induction required continuous protein synthesis, being completely inhibited by addition of the protein synthesis inhibitor cycloheximide simultaneously with TPA, but only partially inhibited in a time-dependent manner if cycloheximide was added after TPA. Unlike in other cells tested, the jun and c-fos transcription factor mRNAs showed a prolonged biphasic induction response in K562 cells during TPA treatment. This response was associated with enhanced activity of a transfected recombinant reporter plasmid containing binding sites for the jun/fos transcription factor complex (AP-1) similar to the TPA-responsive element (TRE) sequence we found in the EPA/TIMP gene promoter. We suggest that the induction of EPA/TIMP and several other genes specific for the differentiating K562 cells may be a consequence of the sustained activation of immediate early genes encoding transcription factors, such as jun and c-fos.
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PMID:Increased erythroid potentiating activity/tissue inhibitor of metalloproteinases and jun/fos transcription factor complex characterize tumor promoter-induced megakaryoblastic differentiation of K562 leukemia cells. 215 16

Connective-tissue cells produce a family of metalloproteinases which, once activated, can degrade all the components of the extracellular matrix. These potent enzymes are all inhibited by the tissue inhibitor of metalloproteinases (TIMP), and it was thought that the levels of this inhibitor controlled the extracellular activity of these enzymes. We recently detected a new metalloproteinase inhibitor present in culture media of WI-38 fibroblasts. The inhibitor, named 'large inhibitor of metalloproteinases' (LIMP), can be separated from TIMP by gel filtration on Ultrogel AcA 44, where it is eluted with an apparent Mr of 76,000. A portion of this inhibitor-containing peak binds to concanavalin A-Sepharose, indicating that at least some of the inhibitor contains carbohydrate. LIMP inhibits collagenase (MMP-1), stromelysin (MMP-3) and gelatinase (MMP-2) in a dose-dependent fashion. Collagenase forms tight-binding complexes with LIMP, which can be separated from free collagenase on gel-filtration columns. The complex is eluted with Mr 81,600 (AcA 44) or Mr 60,000 (Superose 12). This complex is larger than that formed between collagenase and TIMP, which has Mr 52,800 (Aca 44) or 41,000 (Superose 12). Polyclonal antibody to TIMP does not recognize LIMP by immunoblotting, and will not block the inhibition of collagenase by LIMP, showing that LIMP is not a multimeric form of TIMP. The role of this new inhibitor in connective-tissue breakdown studies and its relationship to previously described inhibitors of metalloproteinases is discussed.
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PMID:Identification of a new metalloproteinase inhibitor that forms tight-binding complexes with collagenase. 216 93

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

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

Stromelysin is a metalloproteinase that degrades extracellular matrix macromolecules including fibronectin, laminin, collagen IV and proteoglycans. We now report that cycloheximide, an inhibitor of protein synthesis, induces human stromelysin mRNA in fibroblast cultures in a time- and dose-dependent fashion. As determined by Northern hybridization, a 24-h treatment with cycloheximide increased stromelysin mRNA about 20-fold over the control level. In vitro translation or translation in cells after removal of cycloheximide resulted in increased levels of immunoprecipitable stromelysin suggesting that the cycloheximide-induced stromelysin mRNA was functional. Analysis of mRNA stability suggested that the cycloheximide effect is in part due to the increased activation of the stromelysin gene. In contrast to these results, cycloheximide did not induce collagenase mRNA but, rather, prevented its induction by interleukin-1 beta. These data provide evidence for discoordinate regulation of collagenase and stromelysin genes and suggest that a short-lived repressor protein may play a role in the stromelysin gene expression.
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PMID:Cycloheximide induces stromelysin mRNA in cultured human fibroblasts. 216 19


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