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)

Progressive renal fibrosis is considered to be the final common pathway leading to chronic renal insufficiency. In this study, the authors examined some of the cellular and molecular mechanisms regulating the renal accumulation of extracellular matrix (ECM) proteins using rats with puromycin amino-nucleoside (PAN) nephrosis as an acute model system. Puromycin aminonucleoside rats developed reversible nephrotic syndrome accompanied by an interstitial infiltrate of monocytes. The number of interstitial fibroblasts expressing ST4 antigen did not increase. During the first 4 days, steady-state mRNA levels for all genes examined remained at or below control levels. At 1 week, nephrotic syndrome and interstitial inflammation were established, and a period of renal cell proliferation occurred, identified by increased histone mRNA levels and localized by tritiated thymine autoradiography to tubular epithelial cells and occasional interstitial cells. Transforming growth factor-beta (TGF-beta) steady-state mRNA levels were increased eightfold, but returned to control levels by 3 weeks. At week 1, there was a 10- to 20-fold increase in kidney steady-state mRNA levels for genes encoding interstitial matrix proteins collagen I and fibronectin and basement membrane collagen IV. By in situ hybridization, alpha 1(I) procollagen mRNA was localized to interstitial cells. Immunofluorescence microscopy demonstrated focal accumulation of ECM proteins in the tubulointerstitial compartment at 2 and 3 weeks, but by 6 weeks, kidney immunohistology was normal again. Steady-state mRNA levels for the matrix degrading metalloproteinase stromelysin remained at control values, whereas the levels for interstitial collagenase were normal at week 1 and increased twofold to threefold at 2 and 3 weeks. Steady-state mRNA levels for the tissue inhibitor of metalloproteinases (TIMP) increased fivefold at 1 week and returned to baseline values over the next 2 weeks. The results of this study suggest that tubulointerstitial ECM accumulation occurs in rats with acute PAN nephrosis because of the activation of genes encoding several matrix proteins and inhibition of matrix degradation mediated by TIMP. These events are reversed during the phase of recovery from nephrotic syndrome. Increased mRNA levels for TGF-beta, possibly originating from inflammatory interstitial monocytes, are likely to be one of the mediators of the molecular events observed.
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PMID:Renal extracellular matrix accumulation in acute puromycin aminonucleoside nephrosis in rats. 128 19

Secreted metalloproteases initiating proteolytic degradation of collagens and proteoglycans play a critical role in remodeling of the connective tissue. Activation of the secreted proenzymes and interaction with their specific inhibitors TIMP and TIMP-2 are responsible for regulation of enzyme activity in extracellular space. We have previously demonstrated that 92- and 72-kDa Type IV procollagenases, in contrast to interstitial collagenase (ClI), form specific complexes with TIMP and the related inhibitor TIMP-2, respectively. The physiologic significance of the proenzyme-inhibitor complex and the mechanism of activation of Type IV collagenases remained unclear. Here, we demonstrate that in the absence of TIMP, 92-kDa Type IV procollagenase (92T4Cl) can form a covalent homodimer and a novel complex with ClI. In the presence of TIMP, the formation of a 92T4Cl proenzyme complex with TIMP prevents dimerization, formation of the complex with ClI, and activation of the 92T4Cl proenzyme by stromelysin, a related metalloprotease. The proenzyme homodimer is unable to form a complex with TIMP. All TIMP-free forms of the proenzyme can be activated by stromelysin. The 92T4Cl-ClI complex can be activated to yield a complex active against both gelatin and fibrillar Type I collagen, suggesting a mechanism for cooperative action of two enzymes in reducing collagen fibrils to small peptides under physiologic conditions.
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PMID:Interaction of 92-kDa type IV collagenase with the tissue inhibitor of metalloproteinases prevents dimerization, complex formation with interstitial collagenase, and activation of the proenzyme with stromelysin. 131 14

Recombinant human interstitial collagenase, an N-terminal truncated form, delta 243-450 collagenase, recombinant human stromelysin-1, and an N-terminal truncated form, delta 248-460 stromelysin, have been stably expressed in myeloma cells and purified. The truncated enzymes were similar in properties to their wild-type counterparts with respect to activation requirements and the ability to degrade casein, gelatin, and a peptide substrate, but truncated collagenase failed to cleave native collagen. Removal of the C-terminal domain from collagenase also modified its interaction with tissue inhibitor of metalloproteinases-1. Hybrid enzymes consisting of N-terminal (1-242) collagenase.C-terminal (248-460) stromelysin and N-terminal (1-233) stromelysin.C-terminal (229-450) collagenase, representing an exchange of the complete catalytic and C-terminal domains of the two enzymes, were expressed in a transient system using Chinese hamster ovary cells and purified. Both proteins showed similar activity to their N-terminal parent and neither was able to degrade collagen. Analysis of the ability of the different forms of recombinant enzyme to bind to collagen by ELISA showed that both pro and active stromelysin and N-terminal collagenase.C-terminal stromelysin bound to collagen equally well. In contrast, only the active forms of collagenase and N-terminal stromelysin.C-terminal collagenase bound well to collagen, as compared with their pro forms.
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PMID:The role of the C-terminal domain in collagenase and stromelysin specificity. 131 62

To investigate the role of tumor necrosis factor-alpha (TNF alpha) in advanced collagenolysis and degradation of connective tissue components in preterm parturition, the effects of human recombinant TNF alpha (hrTNF alpha) on the production of matrix metalloproteinase 1 (MMP-1)/tissue collagenase, MMP-3/stromelysin, tissue inhibitor of metalloproteinases (TIMP), urokinase type-plasminogen activator (uPa) and prostaglandin (PG) E2 in human chorionic cells were examined in vitro. Human chorionic cells, but not amniotic cells, were found to respond to macrophage-conditioned medium (contains mainly interleukin 1) to produce MMP-1 and MMP-3. This indicated that the chorionic cell is one of the MMP-producing cells of fetal membranes. When confluent chorionic cells were treated with hrTNF alpha, the production of MMP-1 and MMP-3 as well as of uPa and PGE2 was greatly increased in a dose-dependent manner. In contrast, the production of TIMP was suppressed by hrTNF alpha. These results suggested that TNF alpha may participate in destruction of collagen and other connective tissue matrix components of fetal membranes and in promotion of uterine contractility in preterm parturition with intraamniotic infection.
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PMID:Tumor necrosis factor-alpha stimulates the biosynthesis of matrix metalloproteinases and plasminogen activator in cultured human chorionic cells. 131 22

The interstitial collagenase gene (CLG), one of the main candidates in severe generalized recessive epidermolysis bullosa dystrophica (SGREBD), is closely linked to the stromelysin-1 (STMY1) and stromelysin-2 (STMY2) genes. These three loci map on chromosome 11 (q21-q22.3), where they constitute a cluster of genes coding for metalloproteinases involved in the degradation of the extracellular matrix (ECM). A recessive form of cerebellar ataxia of post-puberal onset (CLA1) has also been assigned to chromosome 11 (q14-q21). Since useful restriction fragment length polymorphisms (RFLPs) for the CLG gene are not available, we have studied the inheritance of the marker TaqI RFLP of the STMY1 gene in a North Italian family with a child affected by SGREBD, and his two sisters showing cerebellar ataxia (CA) of post-puberal onset. We have also studied the MspI RFLP of the fibronectin gene (FN1), which is located on chromosome 2q34-q36, and which codes for non-collagenous matrix proteins. Since we did not observe the segregation of the pathological phenotypes with STMY1 and FN1 RFLPs, we excluded the involvement of these genes in both the SGREBD and CA present in this family. The exclusion of the STMY1 gene indicates that the mutation causing SGREBD cannot be located in the CLG and/or STMY2 genes because of their proximity to the STMY1 locus. These data also indicate that the CA form here reported is not attributable to alterations in regions close to the collagenase cluster on chromosome 11.
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PMID:Exclusion of stromelysin-1, stromelysin-2, interstitial collagenase and fibronectin genes as the mutant loci in a family with recessive epidermolysis bullosa dystrophica and a form of cerebellar ataxia. 135 52

The effects of the chondroprotective drugs, sodium pentosan polysulphate (SP54) and Arteparon (glycosaminoglycan polysulphate), on the in vitro activities of the purified matrix metalloproteinases interstitial collagenase (matrix metalloproteinase 1, MMP1) and stromelysin (MMP3) were examined. Both drugs produced concentration-dependent enhancement of the degradation of type I collagen fibrils by purified human fibroblast collagenase and rat tumour collagenase. Rat collagenase activity was increased by drug concentrations above 0.5 microgram/mL, whereas human collagenase activity was only increased by higher drug concentrations, above 5 micrograms/mL. The concentration dependence of the increase in rat collagenase activity was similar for both drugs, with a maximal 3-fold increase at 50 micrograms/mL. In contrast, human collagenase activity was increased to a greater extent by SP 54 compared to Arteparon, with maximal increases at 5000 micrograms/mL of 6-fold and 2-4-fold, respectively. Both drugs produced concentration-dependent inhibition of the proteoglycan-degrading activity of both human fibroblast stromelysin and rat tumour stromelysin. Rat and human stromelysin activities were inhibited at drug concentrations above 0.005 microgram/mL, with a similar concentration dependence for both drugs. Fifty percent inhibition of rat stromelysin was produced by concentrations of each drug in the 0.5-5 microgram/mL range. The pattern of inhibition of human stromelysin was similar, except that drug concentrations in the 500-5000 micrograms/mL range produced 50% inhibition. The possible modes of action for these drug effects and their possible pharmacological significance are discussed.
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PMID:The chondroprotective drugs, Arteparon and sodium pentosan polysulphate, increase collagenase activity and inhibit stromelysin activity in vitro. 138 3

Leukoregulin (LR), a product of activated T-cells, has been recently shown to modulate the metabolism of extracellular matrix components in human skin fibroblast cultures (Mauviel et al., J Cell Biol 113:1455-1462, 1991). In this study we focused our attention on the effects of LR on the expression of stromelysin-1 gene. This matrix metalloprotease has a broad spectrum of degradative activity and it is also required for maximal activation of interstitial collagenase. Incubation of skin fibroblast cultures with LR resulted in a dose- and time-dependent elevation of stromelysin-1 mRNA levels, the maximum enhancement being up to approximately sevenfold. This effect was abolished by cycloheximide, suggesting a requirement for ongoing protein synthesis. Transient cell transfections with a promoter/reporter gene construct containing 1.3 kb of 5' flanking DNA of the human stromelysin-1 gene linked to the chloramphenicol acetyl transferase (CAT) gene, indicated enhancement of promoter activity by LR. This enhancement was abolished by a single base substitution in the AP-1 binding site of the promoter. Furthermore, gel mobility shift assays demonstrated enhanced AP-1 binding activity in nuclear extracts from cells incubated with LR. However, LR did not alter the activity of a construct containing three AP-1 sequences in front of the thymidine kinase promoter linked to the CAT gene. These results collectively suggest that activation of stromelysin-1 gene expression by LR is mediated by AP-1 regulatory elements which are necessary, but not sufficient, for gene response.
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PMID:Leukoregulin, a T-cell derived cytokine, upregulates stromelysin-1 gene expression in human dermal fibroblasts: evidence for the role of AP-1 in transcriptional activation. 142 74

Vascular endothelial growth factor (VEGF) is a 45kDa secreted peptide that has potent mitogenic activity specific for endothelial cells in vitro and the ability to induce a strong angiogenic response in vivo. In the present study, 24 h treatment with VEGF resulted in a stimulation of expression of the metalloproteinase, interstitial collagenase, at the protein and mRNA levels 2.5-3.0-fold in human umbilical vein endothelial cells but not in human dermal fibroblasts. The dose response curve for collagenase induction was biphasic with the peak stimulatory response obtained by treatment of cells with 10-100 ng/ml (0.2-2 nM) VEGF. The dose response curve for collagenase induction overlapped with, but was not identical to, the response curve for proliferation, which showed VEGF mitogenic activity between < or = 0.1-50 ng/ml (< or = 0.002-1 nM). There was no induction seen in expression of other members of the matrix metalloproteinase family, including the 72kDa type IV collagenase, the 92kDa type V collagenase, or stromelysin. Expression of transcripts for the major metalloproteinase inhibitor, tissue inhibitor of metalloproteinases, was also unaltered by treatment with VEGF (1-200 ng/ml). These studies demonstrate that in addition to stimulating proliferation of endothelial cells, VEGF can also induce the expression of the only metalloproteinase that can initiate degradation of interstitial collagen types I-III under normal physiological conditions. Both responses are likely to contribute to the angiogenic potential of this peptide.
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PMID:Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. 144 17

Extracellular matrix metalloproteases are synthesized as proenzymes and are activated by certain physiological agents after secretion into the extracellular space. The identity of these agents and the stimulus that elicits their response in vivo is only recently becoming clear, but a variety of agents or stimuli are capable of activating these metalloproteases in vitro also. Of these, the most well studied and characterized are trypsin, plasmin and the organomercurials. These agents appear to have in common an ability to disrupt the structure of the stable latent enzyme in such a way as to allow the generation of a proteolytic active site. In the case of organomercurial activation, intramolecular proteolytic cleavage of the amino-terminus of the enzyme occurs subsequent to generation of activity. A similar intramolecular process is seen with trypsin and plasmin activation except that it is initiated by a single trypsin or plasmin catalyzed cleavage in the amino-terminus prior to the autocatalytic cleavages. A possible explanation for organomercurial activation is that the mercurial disrupts a cysteinyl residue coordination bond with the active site zinc that prevents interaction with substrate. Disruption of this complex would allow productive enzyme-substrate interaction via the newly available coordination site. In addition, activated stromelysin is capable of increasing the specific activity of active interstitial collagenase by approximately ten-fold through what appears to be proteolytic removal of a small peptide.
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PMID:Activation of extracellular matrix metalloproteases by proteases and organomercurials. 148 30

The zymogens of matrix metalloproteinase 1 (MMP-1: tissue collagenase), MMP-2 (gelatinase/type IV collagenase) and MMP-3 (stromelysin) were purified from the culture medium of human rheumatoid synovial fibroblasts and the mechanisms of activation of each zymogen by proteinases and 4-aminophenylmercuric acetate (APMA) were studied by kinetic and sequence analyses. The treatment of proMMP-1 (M(r) = 52,000) with proteinases or APMA converted the zymogen to M(r) = 43,000, but it exhibited only 14-25% of the maximal activity. Incubation of a partially active MMP-1 with MMP-3 resulted in rapid, full activation by generating the 41,000-M(r) MMP-1 with Phe81 as the NH2-terminus. MMP-3 directly activated proMMP-1 by cleaving the Gln80-Phe81 bond, but this reaction was extremely slow, indicating that the Gln80-Phe81 bond is not readily available to MMP-3 in the native proMMP-1 molecule. ProMMP-2 (M(r) = 72,000) was activated only by APMA, but not by proteinases. The activation by APMA was rapid and generated an active MMP-2 of M(r) 68,000, but the enzymic activity declined rapidly after activation by autolysis. The NH2-terminal sequence analysis of active MMP-2 indicated that the Asn80-Tyr81 bond was cleaved upon APMA treatment. In contrast, proMMP-3 (M(r) = 57,000) was activated by a variety of proteinases with different specificities. The initial attacks of these proteinases are on a stretch of highly charged groups at the position 34-39 in the propeptide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation mechanisms of the precursors of matrix metalloproteinases 1, 2 and 3. 148 33


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