EC:3.4.24.17 - FACTA Search

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)

Endothelial-cell-stimulating angiogenesis factor (ESAF) has been shown to activate procollagenase and reactivate complexes of collagenase and gelatinase A with tissue inhibitor of metallo-proteinase (TIMP)-1. In the present paper we show a purification protocol for bovine pineal ESAF and that purified ESAF activates progelatinase A and prostromelysin-1. Unlike the activation of procollagenase by plasmin/plasminogen activator, which requires the presence of stromelysin for full activation, ESAF is able to activate fully all three proenzymes. Purified ESAF is also shown to reactivate the complexes of gelatinase A, collagenase and stromelysin-1 with TIMP-2. Once separated, both enzyme and inhibitor are active; however, ESAF binds to the enzyme in a manner preventing it from further inhibition by TIMP. ESAF is the only physiological molecule able to reactivate the TIMP/enzyme complex.
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PMID:Endothelial-cell-stimulating angiogenesis factor (ESAF) activates progelatinase A (72 kDa type IV collagenase), prostromelysin 1 and procollagenase and reactivates their complexes with tissue inhibitors of metalloproteinases: a role for ESAF in non-inflammatory angiogenesis. 876 Mar 57

Previous studies have shown that costochondral cartilage cell cultures produce extracellular matrix vesicles which contain metalloproteinase activity. In the present study, we examined whether two matrix metalloproteinases (MMPs) known to be present in cartilage, stromelysin-1 and 72 kDa gelatinase, are expressed by fourth passage resting zone and growth zone costochondral chondrocytes and whether they are specifically incorporated into matrix vesicles produced by the cells. We also examined whether the cells synthesize tissue inhibitor of metalloproteinase-1 and -2 (TIMP-1 and TIMP-2). Oligonucleotide primers for stromelysin-1, 72 kDa gelatinase, tissue inhibitor of metalloproteinases-1 and -2 (TIMP-1 and TIMP-2), and GAPDH were synthesized and optimized for use in the reverse transcription-polymerase chain reaction (RT-PCR). It was found that both resting zone and growth zone chondrocytes produced mRNA for both MMPs and the two TIMPs. Further, immunostaining of cell layers with antibodies to 72 kDa gelatinase and stromelysin-1 showed that both cell types produced these MMPs in culture. Substrate gel electrophoresis and Western analysis were used to characterize MMP activity in matrix vesicles, media vesicles, or plasma membranes as well as in conditioned media produced by the chondrocyte cultures. It was found that matrix vesicles but not plasma membranes or media vesicles were selectively enriched in stromelysin-1. Also, 72 kDa gelatinase was found in matrix vesicles, but to a lesser extent than seen in media vesicles. The relative activity of each enzyme detected was cell maturation-dependent. No MMP activity was detected in conditioned media produced by either cell type. The results of this study show that MMPs are expressed by resting zone and growth zone chondrocytes in culture and differentially distributed among three different membrane compartments. This suggests that, in addition to the well-known activators and inhibitors of MMP activity in the matrix, differential membrane distribution may enable more precise control over the site, rate, and extent of matrix degradation by the cell.
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PMID:Chondrocyte cultures express matrix metalloproteinase mRNA and immunoreactive protein; stromelysin-1 and 72 kDa gelatinase are localized in extracellular matrix vesicles. 876 42

We examined production and tissue localization of matrix metalloproteinase (MMP)-1 (tissue collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin-1), MMP-9 (gelatinase B), tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in human breast carcinomas. In more than half of the cases, MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2 were immunolocalized in carcinoma cells and MMP-2 was on the carcinoma cell membranes as well, whereas MMP-3 was positively stained in less than 15% of the cases. MMP-1 staining in carcinoma cells was significantly higher in scirrhous carcinoma than in other types of carcinoma. MMP-9 expression was remarkably higher in the carcinoma cases with lymphnode metastasis than in the non-metastatic cases. MMP-3 was mainly expressed in T-lymphocytes infiltrated in the tumor stroma. Stromal fibroblasts were positive for all these MMPs except for MMP-3. The TIMP-1 levels released into the culture media by carcinoma tissues were significantly lower than those by fibroadenoma tissues, although there were no significant differences in the levels of MMP-1, MMP-2, MMP-9 and TIMP-2. Gelatin zymographical analyses showed that the activation rate of the zymogen of MMP-2 (proMMP-2) is significantly higher in the more advanced carcinoma group with lymphnode metastasis than in the metastasis-negative and fibroadenoma groups. These data indicate that MMP-1, MMP-2 and MMP-9 are highly expressed in human breast carcinoma tissue and suggest that activation of proMMP-2 may be an indicator of lymphnode metastasis of the breast carcinoma.
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PMID:Production of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human breast carcinomas. 876 24

Thickening of the tubular basement membrane is one of the hallmarks of the polycystic kidney disease (PKD). The present study was conducted to investigate the potential role of the matrix metalloproteinase-2 (MMP-2) and its specific tissue inhibitors (TIMP-1 and TIMP-2) in the accumulation of matrix components in PKD. As a model of PKD, two-month-old heterozygous Han:SPRD rats, which are at an early stage of cystogenesis, were used. MMP-2, but not MMP-9 (gelatinase B) nor MMP-3 (stromelysin) could be detected in proximal tubules of the normal rat kidney. The presence of the inhibitors TIMP-1 and TIMP-2 was confirmed on the mRNA level. In tubules from PKD rats MMP-2 activity was lower (31 +/- 8 vs. 58 +/- 7 U/prep., N = 9, P < 0.05), mRNA of MMP-2 was reduced 4.2 +/- 0.6-fold (N = 4, P < 0.05) and enzyme protein was depressed 3.8 +/- 0.8-fold (N = 4, P < 0.05). By contrast, TIMP-1 mRNA was 9.0 +/- 1.1-fold and TIMP-2 mRNA 3.8 +/- 0.7-fold (N = 4, P < 0.05) elevated over controls. Cyst fluid from homozygous rats contained MMP-2 protein and activity. These findings indicate that tubular MMP-2 activity is reduced in PKD, due to down-regulation of MMP-2, up-regulation of TIMP-1 and TIMP-2, and luminal secretion of the enzyme. It is conceivable that these alterations relate to the enhanced matrix accumulation observed in the evolution of PKD.
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PMID:Tubular gelatinase A (MMP-2) and its tissue inhibitors in polycystic kidney disease in the Han:SPRD rat. 877 Sep 51

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases which are secreted from cells as zymogens and can be activated by treatment with organomercurial reagents or limited proteolysis. The proenzyme forms of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) are found in complex with tissue inhibitor of metalloproteinases (designated proMMP-2/ TIMP-2 and proMMP-9/TIMP-1, respectively). The proposed mechanism of activation by mercurial compounds involves the induction of a conformational change in the zymogen which leads to propeptide autoprocessing. To investigate the possibility of conformational differences in MMPs, solute quenching of MMP intrinsic fluorescence was used to probe the relative exposure of tryptophan residues in latent and mercurial-activated MMPs. Our data demonstrate that fluorescence quenching of the proMMP-2/TIMP-2 complex by either acrylamide or iodide is significantly increased following mercurial activation. In contrast, no significant change in tryptophan accessibility accompanies mercurial treatment of either proMMP-2 or TIMP-2 alone, or mercurial-activated MMP-2 mixed with TIMP-2. To determine whether the enhanced fluorescence quenching was unique to the activated proMMP-2/TIMP-2 complex, similar experiments were performed using MMP-1, MMP-3, and MMP-9/TIMP-1 complex. In all cases, both latent and mercurialtreated MMPs exhibited similar fluorescence quenching profiles, suggesting that there are no significant conformational differences between the zymogen and activated forms of MMP-1, -2, -3, or -9/TIMP-1. The enhanced fluorescence quenching observed with mercurial-treated proMMP-2/TIMP-2 is indicative of increased exposure of a previously buried tryptophan residue(s), providing evidence for a structural rearrangement of the activated complex. These data, together with our previous biochemical observation that mercurial treatment of proMMP-2/TIMP-2 exposes the MMP-2 active site without propeptide processing (Y. Itoh et al. (1995) Biochem. J. 308, 645-651), suggest that the activated proMMP-2 in the complex may represent a transitional conformational intermediate in MMP activation.
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PMID:Fluorescence quenching studies of matrix metalloproteinases (MMPs): evidence for structural rearrangement of the proMMP-2/TIMP-2 complex upon mercurial activation. 880 67

Programmed cell death in mammary tissue was studied during natural weaning in lactating mice and after litter removal or milk stasis. All treatments stimulated mammary apoptosis, indicating that this process is an integral part of the tissue's involution after lactation. Induction of apoptosis was slower in natural weaning than after litter removal but occurred earlier when mice were concurrently pregnant during natural weaning. Ipsilateral induction of apoptosis by milk stasis in teat-sealed glands indicates that cell death is under local (i.e., intramammary) as well as endocrine regulation. Apoptosis detected by DNA laddering was associated with changes in expression of p53 and bax, two genes implicated in the regulation of cell death, and was accompanied by structural degeneration characteristic of mammary involution. Reciprocal changes in stromelysin mRNA, and that of its inhibitor TIMP-2, suggested that this structural reorganisation was the result of coordinated changes in gene expression favouring proteolysis of the extracellular matrix.
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PMID:Programmed cell death during mammary tissue involution induced by weaning, litter removal, and milk stasis. 881 10

Restructuring of basement membranes is a hallmark of the pathology of renal cystic disorders. Here, we present findings consistent with the view that basement membrane degradation by matrix metallo-proteinases (MMPs) may contribute to abnormal basement membrane structure in polycystic kidney disease. Cells from cystic kidney tubules embedded in collagen gels appeared to migrate through the gel. This migration through collagen indicated that these cells could degrade the matrix. To examine this activity, we cultured cystic kidney tubules derived from the C57BL/6J cpk/cpk mouse, a hereditary model of polycystic kidney disease, and assayed conditioned medium for the presence of MMPs and tissue inhibitors of metalloproteinases (TIMPs). The conditioned medium from the cystic tubules contained higher than normal levels of MMP-9, MMP-2, and MMP-3 as well as TIMP-1 and TIMP-2. A 101 kDa protease was present equally in cystic and control cultures and although inhibited by EDTA, it was not inhibited by TIMPs, nor activated by the mercurial compound APMA. These data suggest that cystic kidney tubules synthesize and secrete high levels of MMPs which may then participate in the restructuring of the tubular basement membrane.
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PMID:Matrix metalloproteinases and TIMPS in cultured C57BL/6J-cpk kidney tubules. 887 58

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

In a wide variety of tumor types, the expression of stromelysin 1 which is one of the matrix metalloproteinases (MMPs) has been shown to correlate with tumor invasion. However, little is known about the distribution of stromelysin in human brain tumors. We have previously shown that a correlation exists between the type IV collagenases, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 transcripts and in vitro invasiveness among 7 human astrocytoma cell lines. In the present study, we analyzed the expression of stromelysin 1 among the same panel of human astrocytoma cell lines and human fibroblasts by northern blot analyses and in situ hybridization. Northern blot analysis demonstrated that SF-126 and U87 MG expressed high level stromelysin 1 transcripts. Following heat shock stimulation, the stromelysin 1 transcript was up-regulated in U87 MG astrocytoma cells. In situ hybridization analysis showed specific intracytoplasmic localization of mRNA for stromelysin in these astrocytoma cell lines. By casein zymography, we have determined that both SF-126 and U87 MG secreted stromelysin 1 protein. We conclude that stromelysin 1 is expressed by certain human astrocytoma cell lines, and this study confirms the importance of continuing to characterize the proteolytic enzyme profile of these tumors to fully understand the molecular mechanisms involved in astrocytoma invasiveness.
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PMID:Expression of stromelysin 1 in human astrocytoma cell lines. 894 93

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) play an important role in tissue destruction and remodeling. Nine samples of cement interface tissues from nine patients who had failed cemented total hip arthroplasty (THA) were obtained for revision of THA and analyzed on mRNA expression of MMPs and TIMPs. The preoperative serial radiographic examinations revealed an apparent clear zone around all implants. We excluded septic loosening as one of the factors affecting THA. Three samples were obtained from three different sites of the acetabular interface tissue in each patient. After extraction of total RNA from 27 samples, we used the reverse-transcriptional polymerase chain reaction (RT-PCR). mRNA of MMP-1, -2, -3, -9, and TIMP-1 and -2 was detected in the interface tissue. MMP-10 mRNA was not detected, yet MMP-1 and MMP-3 mRNA were commonly observed. TIMP-2 mRNA was also strongly expressed compared to TIMP-1. It was thus demonstrated that MMPs and TIMPs were produced locally in the cemented tissue of THA loosening. These findings may suggest that MMPs and TIMPs expressed around the implants play a critical role in the progression of aseptic loosening of THA.
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PMID:mRNA expression of matrix metalloproteinases and tissue inhibitors of metalloproteinase in interface tissue around implants in loosening total hip arthroplasty. 895 51

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