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)

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 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

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

The effects of a specific calmodulin inhibitor, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) on the synthesis of tissue inhibitor of metalloproteinases (TIMP) and precursor of matrix metalloproteinase 1/tissue collagenase (proMMP-1) and matrix metalloproteinase 3/stromelysin (proMMP-3), were examined using human uterine cervical fibroblasts in culture. When the cells were treated with human recombinant interleukin 1 alpha, the synthesis of TIMP, proMMP-1, and proMMP-3 was greatly enhanced along with the increase in the steady-state levels of mRNAs for respective proteins. The treatment of the cells with human recombinant interleukin 1 alpha and W-7 further augmented the production of proMMPs-1 and -3 and the accumulation of their mRNAs. In contrast, TIMP production and its steady-state mRNA level were reduced considerably under these conditions. Similar observations were made with another calmodulin inhibitor, trifluoperazine, but not with N-(6-aminohexyl)-1-naphthalenesulfonamide, the weakest inhibitor for calmodulin. These results indicate that calmodulin is required for the interleukin 1-enhanced synthesis of TIMP but it is a suppressor for the synthesis of proMMPs-1 and -3.
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PMID:Calmodulin differentially modulates the interleukin 1-induced biosynthesis of tissue inhibitor of metalloproteinases and matrix metalloproteinases in human uterine cervical fibroblasts. 164 24

The production of the precursor of tissue collagenase/matrix metalloproteinase 1 (proMMP-1) by cultured human aortic medial smooth muscle cells (SMCs) was significantly enhanced by the treatment of the cells with platelet-derived growth factor (PDGF), interleukin 1 or 12-O-tetradecanoylphorbol-13-acetate (TPA). The response to PDGF of SMCs exhibited a tendency to be age-dependent: only SMCs obtained from older individuals (age: 54, 56, 72 and 74 years) responded to PDGF and synthesized proMMP-1, but not SMCs from young individuals (age: 10, 16 and 41 years), and weak responsiveness with a 19-year-old individual. On the other hand, induction of proMMP-1 synthesis in SMCs by TPA was not discriminated by age. The synthesis of two other related matrix metalloproteinases was also examined. Matrix metalloproteinase 2 was found to be constitutively expressed in zymogen form in SMCs and its synthesis was not affected by the treatments with PDGF, interleukin 1 or TPA. The synthesis of matrix metalloproteinase 3 (stromelysin) was not detected in SMCs from both young and old individuals even after the treatment with PDGF, interleukin-1, prostaglandin E2 or TPA. The ability of SMCs to synthesize and secrete proMMP-1 in response to PDGF suggests that this enzyme plays an important role in the migration of PDGF-stimulated SMCs from the media into the intima of aorta and the eventual formation of atherosclerotic plaques.
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PMID:Production of tissue collagenase (matrix metalloproteinase 1) by human aortic smooth muscle cells in response to platelet-derived growth factor. 166 62

Types I to VI collagens were immunolocalized in normal and rheumatoid synovium using monospecific antibodies. Immunofluorescence studies showed type VI in the extracellular matrix of the lining cell layer, whereas positive staining for type III collagen was observed in both the lining and sublining cell layers. All other collagens could not be detected in the lining cell layer. Immunogold staining of the rheumatoid synovium localized type VI collagen to filamentous material, which was the major extracellular structure of the lining cell layer. Type III collagen was associated with thin cross-striated collagen fibrils. A brief treatment of rheumatoid synovial tissue with bacterial collagenase produced in the lining cell layer numerous broad-banded fibrils with 100-nm periodicity; these fibrils could be labeled with the antibody against type VI collagen. This suggests that type VI collagen filaments have the potential to form periodic structures under certain conditions. We further studied the susceptibility of type I to VI collagens to matrix metalloproteinase 1, 2 and 3 (collagenase, gelatinase of molecular weight 72,000, stromelysin), which are secreted by synovial lining cells in rheumatoid synovium, and found only type VI collagen to be completely resistant to all these metalloproteinases. These data indicate that type VI collagen, which has the ability to bind to cells and to interstitial collagens, plays an important role in supporting the synovial lining cells in the normal and rheumatoid synovium.
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PMID:localization of type VI collagen in the lining cell layer of normal and rheumatoid synovium. 223 13

Membrane type matrix metalloproteinase 1 (MT-MMP1), a novel 63-kDa member of the matrix metalloproteinase family, is a membrane-anchored enzyme and an activator for gelatinase A. In addition to its C-terminal hydrophobic transmembrane domain, MT-MMP1 has an insertion of 11 amino acids between its propeptide and catalytic domain encrypted with a RRKR recognition motif for the paired basic amino acid cleaving enzyme, furin. In this report, we investigated whether the cleavage of the RRKR motif of MT-MMP1 by Golgi-associated furin is analogous to a similar enzyme activation mechanism observed with stromelysin-3. Mutant forms of MT-MMP1 were cotransfected into COS-1 cells with cDNAs for pro-gelatinase A and/or furin. Immunoprecipitation and immunoblotting using specific antibodies were employed to characterize cell proteins. Whereas furin readily cleaved soluble MT-MMP1 lacking the transmembrane domain (DeltaMT-MMP1), a soluble stromelysin-1/DeltaMT-MMP1 chimera without the RRKR basic motif was resistant to furin-induced cleavage. COS-1 cells cotransfected with wild type MT-MMP1 cDNA and furin cDNA demonstrated a 63-kDa protein (latent enzyme) on SDS-polyacrylamide gel electrophoresis rather than the anticipated lower molecular weight activated enzyme. Inhibition of furin activity with alpha1-protease inhibitorPittsburgh (a furin inhibitor) did not affect the pro-gelatinase A activation mechanism in COS-1 cells cotransfected with MT-MMP1 and pro-gelatinase A cDNAs. Furthermore, substitution of the RRKR motif of MT-MMP1 with alanine residues by site-directed mutagenesis resulted in the same 63-kDa protein without loss of pro-gelatinase A activation function. These data indicate that furin-induced activation of MT-MMP1 is not a prerequisite for pro-gelatinase A activation. The mechanism of activation of cell-bound MT-MMP1 remains to be elucidated.
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PMID:Membrane type matrix metalloproteinase 1 activates pro-gelatinase A without furin cleavage of the N-terminal domain. 893 68

Matrix metalloproteinases (MMP) are proteolytic enzymes that play a key role in tissue remodelling during physiological and pathological processes, by initiating the degradation of extracellular matrix. MMP overexpression can lead to tissue destruction which is characteristic of chronic inflammatory diseases such as rheumatoid arthritis and scleritis. Plasma cells are often abundant at such sites of chronic inflammation. In the present study we investigated whether plasma cells could contribute to matrix degradation by their expression of MMP In situ hybridization and immunohistochemical analyses on diseased synovial and scleral tissue demonstrated the expression of stromelysin-1 (MMP-3) and gelatinase B (MMP-9), but little or no tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) mRNA, by IgG-positive plasma cells. Northern blot analysis of RNA extracted from a human plasma cell line (ARH-77), Epstein-Barr virus-transformed B cells, and purified peripheral blood B cells, demonstrated expression of stromelysin mRNA. TIMP-1 mRNA was only detected by the more sensitive reverse transcription PCR method in these cell types. Plasma cells and B lymphocytes cultured in the presence of monensin demonstrated cytoplasmic gelatinase B. Gelatin and casein zymography on conditioned media (CM) derived from cytokine treated plasma cells revealed the induction of secreted gelatinase and stromelysin activity. Western blotting confirmed the presence of stromelysin-1 and TIMP-1 proteins in plasma cell CM. These data suggest that plasma cells are not only capable of modulating an inflammatory response by antibody and cytokine production, but also by their ability to produce MMP. Secretion of MMP from focal aggregates of plasma cells may play a critical role in tissue destructive diseases such as rheumatoid synovitis and scleritis.
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PMID:Expression of matrix metalloproteinases by human plasma cells and B lymphocytes. 964 58

The role of extracellular matrix metalloproteinase enzymes and the tissue inhibitors of metalloproteinase in the periprostetic connective tissue matrix of loose artificial hip joints is reviewed. In the periprosthetic granulomatous interface connective tissues between bone and implants and inner cellular regenerating pseudocapsular tissues, matrix metalloproteinase 1, matrix metalloproteinase 2, matrix metalloproteinase 3, matrix metalloproteinase-9, and membrane type 1 matrix metalloproteinase enzymes can be shown in the light of immunohistochemistry, enzyme activity analysis, and messenger ribonucleic acid levels. Tissue inhibitors of metalloproteinase 1 and tissue inhibitors of metalloproteinase 2 also are found in the corresponding tissues. Analysis of matrix metalloproteinase and tissue inhibitors of metalloproteinase interaction shows imbalance between the enzymes and the endogenous inhibitors in favor of matrix metalloproteinase. This induces pathologic connective tissue remodeling in the interface and pseudocapsule. The data suggest that matrix metalloproteinase and tissue inhibitors of metalloproteinase system participate in the extracellular matrix degradation and tissue remodeling in artificial hip joints, and may contribute to the periprosthetic weakening, implant loosening, and osteolysis around implants. More evidence for their active involvement is sought by intervention studies with type specific matrix metalloproteinase inhibitors.
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PMID:Matrix metalloproteinases and tissue inhibitors of metalloproteinases in loose artificial hip joints. 967 31

Treatment of primary cultured chondrocytes from rabbit articular cartilage with interleukin-1 (IL-1)alpha and plasminogen induced the production of pro-matrix metalloproteinase 1 (proMMP-1/interstitial collagenase), proMMP-3 (stromelysin 1) and proMMP-9 (gelatinase B), as well as their active forms. Human urinary trypsin inhibitor (UTI), a multipotent inhibitor of serine proteases, including plasmin inhibited the activation of proMMP-1, proMMP-3 and proMMP-9 when added to the culture medium together with IL-1alpha and plasminogen, in a dose-dependent manner. Moreover, UTI inhibited the release of proteoglycans induced by IL-1alpha and plasminogen from rabbit articular cartilage explants. These findings strongly suggest that UTI inhibits the destruction of articular cartilage induced by plasmin and/or MMPs. Thus, UTI probably exert an anti-osteoarthritic action via inactivation of proMMPs.
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PMID:Human urinary trypsin inhibitor inhibits the activation of pro-matrix metalloproteinases and proteoglycans release in rabbit articular cartilage. 969 50


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