Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The two known mammalian gelatinases, 72- and 92-kDa gelatinase, are extracellular matrix metalloproteinases (MMPs) with a potential role in wound healing. The gelatinase activity as a function of wound age was analysed in tissue extracts of partial- and full-thickness wounds in the skin of pigs, using two assay systems. Total gelatinase activity, assessed using a 3H-labelled gelatin assay, was highest in the early healing phases and then decreased as healing proceeded in both wound types. Gelatin zymography, which distinguishes the activities of the two gelatinases, showed that the 92-kDa (MMP-9) gelatinase essentially followed the same pattern as that of total gelatinase activity, whereas the activity of the 72-kDa gelatinase (MMP-2) remained fairly stable, although it was higher than in uninjured skin, over the experimental period, irrespective of wound type. In conclusion, the two gelatinases appear to have different functions in the wound healing process. The 72-kDa gelatinase (MMP-2) is important during the prolonged remodelling phase, whereas the 92-kDa gelatinase (MMP-9) is linked to the epithelialization process and early repair events.
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PMID:Gelatinase activity during wound healing. 799 93

During early human pregnancy, fetal cytotrophoblasts rapidly invade the uterus. This process has many similarities to tumor invasion, except that the extent and the timing of cytotrophoblast invasion are carefully regulated. Therefore, this system is particularly useful for studying mechanisms that regulate invasive processes. Previously, we showed that production and activation of the 92-kDa type IV collagenase (matrix metalloproteinase(MMP)-9) is necessary for cytotrophoblast invasion in vitro. In other systems, interleukin (IL)-1 beta is an important regulator of matrix-degrading metalloproteinases. Therefore, we investigated trophoblast production of IL-1 beta and its receptors, as well as the effects of this cytokine on cytotrophoblast metalloproteinase activity and invasion. The results showed that release of IL-1 beta parallels the invasive potential of the cytotrophoblasts; the highest levels are produced by first trimester cells and the lowest levels by term cells. Immunoprecipitation showed that cytotrophoblasts express the 80-kDa type I IL-1 receptor, suggesting that autocrine effects are possible. IL-1 beta stimulated trophoblast MMP-9 secretion (by a mechanism that required nascent mRNA and protein synthesis) as well as metalloproteinase activity and invasion of Matrigel. Increasing (by lipopolysaccharide treatment) or decreasing (by glucocorticoid treatment) IL-1 beta production had parallel effects on MMP-9 secretion, metalloproteinase activity, and invasion. Because IL-1 beta and corticosteroids are present in high concentrations at the maternal-fetal interface, normal trophoblast invasion may be regulated, in part, by their opposing actions. In contrast, stimulation of cytotrophoblast IL-1 beta secretion by lipopolysaccharide may play a role in the sequela of infected fetal membranes.
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PMID:Interleukin-1 beta regulates human cytotrophoblast metalloproteinase activity and invasion in vitro. 800 17

The digestion of type I collagen is an essential step in bone resorption. It is well established that osteoclasts solubilize the mineral phase of bone during the resorptive process, but the mechanism by which they degrade type I collagen, the major proteinaceous component of bone, is controversial. Differential screening of a human osteoclastoma cDNA library was performed to characterize genes specifically expressed in osteoclasts. A large number of cDNA clones obtained by this procedure were found to represent 92 kD type IV collagenase (gelatinase B; MMP-9, EC 3.4.24.35), as well as tartrate-resistant acid phosphatase. In situ hybridization localized mRNA for gelatinase B to multinucleated giant cells in human osteoclastomas. Gelatinase B immunoreactivity was demonstrated in giant cells from eight of eight osteoclastomas, osteoclasts in normal bone, and osteoclasts of Paget's disease by use of a polyclonal antiserum raised against a synthetic gelatinase B peptide. In contrast, no immunoreactivity for 72 kD type IV collagenase (gelatinase A; MMP-2, EC 3.4.24.24), which is the product of a separate gene, was detected in osteoclastomas or normal osteoclasts. We propose that the 92 kD type IV collagenase/gelatinase B plays an important role in the resorption of collagen during bone remodeling.
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PMID:Expression of 92 kD type IV collagenase/gelatinase B in human osteoclasts. 803 Apr 43

We have examined the correlation between matrix metalloproteinase (MMP) expression and metastatic properties of a low metastatic osteosarcoma cell line, osteosarcoma takase (OST), under stimulation by tumour necrosis factor alpha (TNF alpha). In vivo, OST cells exhibited significantly increased colonization in the lungs of nude mice in a dose-dependent manner when they were treated by TNF alpha prior to injection. In vitro, TNF alpha enhanced tumour cell invasion through the reconstituted basement membrane in a transwell chamber up to 2.5-fold. Gelatin zymography and sandwich enzyme immunoassays demonstrated marked production of MMP-9 [92-kDa gelatinase/type IV collagenase (gelatinase B)] but not MMP-2 [72-kDa gelatinase/type IV collagenase (gelatinase A)], MMP-3 (stromelysin-1) or MMP-7 (matrilysin). Motility of the tumour cells and adhesion to cultured endothelial cells were slightly increased by the TNF alpha treatment up to 1.6-fold and 1.4-fold, respectively, while the growth rate was decreased. These results suggest that upregulation of MMP-9 together with enhanced motility and endothelial adhesion contribute to the increased metastatic ability of OST cells induced by TNF alpha treatment.
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PMID:Expression of matrix metalloproteinase 9 (92-kDa gelatinase/type IV collagenase) induced by tumour necrosis factor alpha correlates with metastatic ability in a human osteosarcoma cell line. 803 35

Mast cell activation in vivo is often associated with areas of oedema and connective-tissue degradation. Tryptase and chymase are the major serine proteinases released by mast cells, but they appear to have little activity on most components of the extracellular matrix. The matrix metalloproteinases (MMP) are purported to degrade almost all connective tissue elements and are secreted by cells in the form of inactive precursors. Since the mechanisms of MMP activation in vivo are poorly understood we have examined the potential of mast cell proteinases to activate the precursor forms of human collagenase (MMP-1), stromelysin (MMP-3), gelatinase A (MMP-2) and gelatinase B (MMP-9). Mast cell proteinases prepared from purified dog mastocytoma cells were shown to process and activate purified precursor forms of both MMP-1 and MMP-3. Using antipain and chymostatin, inhibitors for tryptase and chymase, respectively, it was demonstrated that both pMMP-1 and pMMP-3 were effectively processed and activated by the chymase component. By contrast, tryptase activated only pMMP-3. The mast cell proteinases were unable to process or activate purified precursor forms of MMP-2 and MMP-9. However, MMP-3 previously activated by mast cell proteinases was shown to activate pMMP-9, but not pMMP-2. Since we have no evidence that mast cells express these four metalloenzymes, the release of mast cell serine proteinases following activation/degranulation could contribute to local metalloproteinase activation and subsequent matrix degradation.
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PMID:Mast cell proteinases activate precursor forms of collagenase and stromelysin, but not of gelatinases A and B. 803 91

The in vitro invasive ability, the expression of cell adhesion molecule E-cadherin, activity of matrix metalloproteinase (MMP) and K-ras point mutation were investigated in eight human endometrial carcinoma cell lines. 1) In vitro invasive abilities of endometrial carcinoma cell lines depend on the degree of cell differentiation and the origin of cell lines. A poorly-differentiated carcinoma cell line (NUE-1) and a cell line derived from metastatic lymph node (SNG-M) were more invasive than moderately-(HEC-1A, HEC-1BE) and well-differentiated (HEC-6, Ishikawa) cell lines. 2) Immunohistochemically, less or non-invasive cell lines expressed E-cadherin strongly, whereas a highly invasive cell line (NUE-1) expressed E-cadherin weakly. 3) When cultured on Matrigel-coated dishes, the tumor cells derived from moderately- and well-differentiated carcinoma aggregated with each other and did not invade Matrigel in the invasion assay. The aggregated cells expressed E-cadherin more strongly when cultured on Matrigel. 4) 72-kD gelatinase (MMP-2) was secreted in serum-free conditioned medium of all cell lines. In an invasive cell line (NUE-1,SNG-M), the activity of MMP-2 was stronger than in other cell lines. And the activity of 92-kDa gelatinase (MMP-9) was detected in most invasive cell line (NUE-1). 5) Point mutation of K-ras codon 12 was detected in four of eight (50%) cell lines by the PCR-RFLP method. The changes in the DNA sequence were identified, but K-ras point mutation was not correlated with in vitro invasiveness of the tumor cells.
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PMID:[The factors involved in invasive ability of endometrial carcinoma cells]. 804 Jun 23

We have explored the tissue localization of extracellular matrix metalloproteinases MMP-1 (fibroblast collagenase), MMP-2 (72-kDa gelatinase/Type IV collagenase), MMP-3 (stromelysin), MMP-8 (polymorphonuclear leukocyte collagenase) and MMP-9 (92-kDa gelatinase/Type IV collagenase) in the tissues around loose hip prostheses. The findings were compared with those in synovial tissues obtained from patients with a fractured femoral neck. MMP-type specific antisera were applied in the sensitive avidin-biotin-peroxidase complex methods. MMP-1 was found in monocyte/macrophages, fibroblasts, and vascular endothelial cells in both interface tissues between bone and acetabular components and the pseudocapsular tissues obtained from loosening of hip prostheses. In these tissues, MMP-8 was occasionally found, but only in polymorphonuclear leukocytes. Cells showing immunoreactivity to 72- and 92-kDa gelatinase/Type IV collagenase, MMP-2 and MMP-9, respectively, and stromelysin, MMP-3, were abundant in both interface and pseudocapsular tissues in loose hip prostheses. In contrast, in hip fractures, immunoreactivity to MMP-1, 2, 3, and 9 was weak and only observed in synovial tissues. Immunoreactivity to MMP-8 was confined to polymorphonuclear leukocytes attached to the synovial membrane or in the infiltrate around blood vessels in the subsynovial connective tissues. The finding of MMP-1, 2, 3, and 9 in the tissues around loose hip prostheses suggests that they play a role in the weakening of connective tissues, and this leads to loosening.
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PMID:Extracellular matrix metalloproteinases around loose total hip prostheses. 804 79

Members of the matrix metalloproteinase (MMP) family have been implicated in disease states such as arthritis, periodontal disease, and tumor cell invasion and metastasis. Stromelysin 1 (MMP-3) has a broad substrate specificity and participates in the activation of several MMP zymogens. We examined known sequences of MMP-3 cleavage sites in natural peptides and proteins and compared sequence specificities of MMP-3 and interstitial collagenase (MMP-1) in order to design fluorogenic substrates that (i) would be hydrolyzed rapidly by MMP-3, (ii) would discriminate between MMP-3 and MMP-1, and (iii) could be monitored continuously without interference from MMP amino acid residues. Designed substrates were then screened for activity toward MMP-1, gelatinase A (MMP-2), MMP-3, and gelatinase B (MMP-9). The first of these substrates, NFF-1 (Mca-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Lys-(Dnp)-Gly, where Mca is (7-methoxycoumarin-4-yl)acetyl and Dnp is 2,4-dinitrophenyl), was hydrolyzed equally well by MMP-3 and MMP-2 (kcat/Km approximately 11,000 s-1 M-1). MMP-1 had 25% of the activity of MMP-3 toward NFF-1. The second substrate, NFF-2 (Mca-Arg-Pro-Lys-Pro-Tyr-Ala-Nva-Trp-Met-Lys(Dnp)-NH2, where Nva is norvaline), was hydrolyzed 60 times more rapidly by MMP-3 (kcat/Km = 59,400 s-1 M-1) than MMP-1. Unfortunately, NFF-2 showed little discrimination between MMP-3, MMP-2 (kcat/Km = 54,000 s-1 M-1), and MMP-9 (kcat/Km = 55,300 s-1 M-1). The third substrate, NFF-3 (Mca-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys(Dnp)-NH2), was hydrolyzed rapidly by MMP-3 (kcat/Km = 218,000 s-1 M-1) and very slowly by MMP-9 (kcat/Km = 10,100 s-1 M-1), but there was no significant hydrolysis by MMP-1 and MMP-2. NFF-3 is the first documented synthetic substrate hydrolyzed by only certain members of the MMP family and thus has important application for the discrimination of MMP-3 activity from that of other MMPs. Although NFF-3 was designed by assuming that substrate subsites were independent and hence free energy changes derived from single mutation experiments were additive, we found discrepancies between predicted and experimental kcat/Km values, one on the order of 2000-5000. Thus, the design of additional discriminatory MMP substrates may require approaches other than assuming additive free energy changes, such as screening synthetic libraries and consideration of secondary and tertiary structures of substrates and the enzyme.
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PMID:Design and characterization of a fluorogenic substrate selectively hydrolyzed by stromelysin 1 (matrix metalloproteinase-3). 806 13

Members of the matrix metalloproteinase (MMP) family have been implicated in the metastasis of tumor cells, but no direct evidence linking any given member of the MMP family to metastatic behavior has been presented. Rat embryo cells transformed by the Ha-ras and v-myc oncogenes or by Ha-ras alone are metastatic in nude mice and release the 92-kDa gelatinase/collagenase (MMP-9), whereas those transformed by Ha-ras plus the adenovirus E1A gene are not metastatic and do not release MMP-9. Here we demonstrate that MMP-9 expression can be induced in these tumorigenic but nonmetastatic rat cells by transfection with an MMP-9 expression vector. Transfection of a MMP-9 expression vector, but not control DNAs, conferred metastatic capacity on the nonmetastatic cells. The majority of colonies isolated after continued passage either in vivo or in vitro had lost the MMP-9 expression vector. However, occasional cells were isolated from metastases which retained MMP-9 expression after passage. These cells retained metastatic capacity. In contrast, cells isolated after losing MMP-9 expression also lost the ability to metastasize. These results provide direct evidence that MMP-9 has a role in tumor metastasis.
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PMID:Direct evidence linking expression of matrix metalloproteinase 9 (92-kDa gelatinase/collagenase) to the metastatic phenotype in transformed rat embryo cells. 818 3

The 92-kDa type IV collagenase (matrix metalloproteinase-9; MMP-9) is frequently expressed in cells showing an invasive nature during physiological and pathological processes, and the expression is strictly controlled by a variety of trans-membrane signals. Binding sites for NF-kB, Sp-1, and AP-1 are reportedly required for induction of MMP-9 gene expression by tumor necrosis factor-alpha or 12-O-tetradecanoylphorbol-13-acetate. Comparison of the sequence of the newly cloned mouse MMP-9 promoter region with our previous human isolate revealed that, in addition to the above mentioned elements, four units of GGGG(T/A)GGGG sequence (GT box) were conserved between the two species. In this study, we have demonstrated that one of the GT boxes located downstream of the AP-1 site is essential along with the AP-1 site for the activation of the promoter by v-Src but not by tumor necrosis factor-alpha or 12-O-tetradecanoylphorbol-13-acetate. Gel mobility-shift assays revealed that binding proteins for retinoblastoma control element, including Sp-1 family protein, can bind specifically to GT boxes. Thus, the v-Src signals to the AP-1 site and to the GT box homologous to retinoblastoma control element acted synergistically in transcriptional activation. These results suggest that certain v-Src-mediated signals are propagated along pathways that are independent of inflammatory cytokines.
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PMID:v-Src activates the expression of 92-kDa type IV collagenase gene through the AP-1 site and the GT box homologous to retinoblastoma control elements. A mechanism regulating gene expression independent of that by inflammatory cytokines. 822 72


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