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At least 361 records · Page 20Linked to original sources
PubMed1998

Regulation of matrix metalloproteinase-2 (gelatinase A, MMP-2), membrane-type matrix metalloproteinase-1 (MT1-MMP) and tissue inhibitor of metalloproteinases-2 (TIMP-2) expression by elastin-derived peptides in human HT-1080 fibrosarcoma cell line.

Soluble kappa-elastin peptides were shown to stimulate the expression of MMP-2 (but not MMP-9) by human fibrosarcoma HT-1080 cells, both at the protein and mRNA levels; maximal effect being observed at a concentration of 25 microg/ml of kappa-elastin. The stimulatory effect could be reproduced using Val-Gly-Val-Ala-Pro-Gly (VGVAPG) peptide, an elastin-derived hydrophobic hexapeptide which represented the elastin receptor binding sequence of tropoelastin. Furthermore, treatment of cells with lactose (30 mM), which dissociated 67-kDa elastin binding protein (EBP) from cell surfaces, completely abolished this effect, suggesting that the elastin receptor could mediate such a response. Using a specific monoclonal antibody, 67-kDa EBP was detected in HT-1080 membrane preparations by Western immunoblotting. Following treatment with 25 microg/ml kappa-elastin or 200 microg/ml VGVAPG, increased levels of the active 62-kDa form of MMP-2 were found in HT-1080 cell extracts. Stimulation of MT1-MMP mRNA expression by treatment with elastin-derived peptides (EDPs) was shown by competitive polymerase chain reaction (PCR). A reverse zymography analysis revealed that EDPs also stimulated TIMP-2 (but not TIMP-1) production by HT-1080 cells. Competitive PCR confirmed increased TIMP-2 mRNA expression by such treatment. These results suggest that occupancy of the 67-kDa elastin receptor by elastin-derived peptides enhanced both expression and activation of proMMP-2 and consequently, could promote the invasive/metastatic ability of tumor cells expressing this receptor.

Elastin↗
PubMed1998

Cloning of the gene for interstitial collagenase-3 (matrix metalloproteinase-13) from rabbit synovial fibroblasts: differential expression with collagenase-1 (matrix metalloproteinase-1).

Cartilage, bone and the interstitial stroma, composed largely of the interstitial collagens, types I, II and III, are remodelled by three members of the metalloproteinase (MMP) family, collagenase-1 (MMP-1), collagenase-2 (MMP-8) and collagenase-3 (MMP-13). MMP-1 and MMP-13 may contribute directly to disease progression, since they are induced in patients with rheumatoid arthritis and osteoarthritis. The study of MMP-1 and MMP-13 gene regulation in models of arthritic disease has been problematic because mice and rats, which are typically used, only possess a homologue of MMP-13. Here we show that in contrast with mice and rats, rabbits possess distinct genes homologous to human MMP-1 and MMP-13. Furthermore, rabbit MMP-13 is expressed simultaneously with MMP-1 in chondrocytes and synovial fibroblasts in response to the cytokines interleukin-1 and tumour necrosis factor-alpha, or the phorbol ester PMA. The time course of MMP-13 induction is more rapid and transient than that of MMP-1, suggesting that distinct mechanisms regulate the expression of these two collagenases. We have cloned the rabbit MMP-13 gene from synovial fibroblasts and demonstrated that the rabbit gene shares greater homology with human MMP-13 than does the mouse interstitial collagenase. Together with the fact that mice and rats do not possess a homologue to human MMP-1, our data suggest that the rabbit provides an appropriate model for studying the roles of interstitial collagenases in connective-tissue diseases, such as rheumatoid arthritis and osteoarthritis.

Amino Acid Sequence↗
PubMed1999

Ovarian carcinoma regulation of matrix metalloproteinase-2 and membrane type 1 matrix metalloproteinase through beta1 integrin.

Culturing DOV 13 ovarian carcinoma cells on three-dimensional collagen lattice but not on thin-layer collagen induces processing of promatrix metalloproteinase (MMP)-2 to a M(r) 62,000 form, suggesting that multivalent integrin aggregation may participate in proteinase regulation. To address the role of collagen-binding integrins in this event, we treated DOV 13 cells with soluble beta1 integrin antibodies (clones P4C10 or 21C8) or beta1 integrin antibodies immobilized on latex beads to promote integrin aggregation. Divalent ligation of beta1 integrins with soluble P4C10 antibodies stimulated expression of pro-MMP-2 and its inhibitor, tissue inhibitor of metalloproteinase-2, whereas soluble 21C8 antibodies had no effect. Aggregation of beta1 integrins with immobilized 21C8 or P4C10 antibodies stimulated MMP-dependent pro-MMP-2 activation and accumulation of a M(r) 43,000 form of membrane type 1 MMP (MT1-MMP), a cell surface activator of pro-MMP-2, in cell extracts. beta1 integrin-mediated MMP-2 activation required protein synthesis and tyrosine kinase signaling and was reduced by an inhibitor of gene transcription. Treatment of control cells with concanavalin A stimulated MMP-dependent pro-MMP-2 activation and accumulation of M(r) 55,000 and 43,000 forms of MT1-MMP in cell extracts. Addition of either the MMP inhibitor GM-6001-X or exogenous tissue inhibitor of metalloproteinase-2 to concanavalin A-treated cells resulted in loss of the M(r) 43,000 form of MT1-MMP and accumulation of the M(r) 55,000 form of the enzyme in cell extracts, suggesting that the M(r) 43,000 form is a product of MMP-dependent M(r) 55,000 MT1-MMP proteolysis. Together, these data suggest that beta1 integrin stimulation of pro-MMP-2 activation involves MT1-MMP posttranslational processing and requires multivalent integrin aggregation.

Collagen↗
PubMedDate not supplied

Limited value of preoperative serum analyses of matrix metalloproteinases (MMP-2, MMP-9) and tissue inhibitors of matrix metalloproteinases (TIMP-1, TIMP-2) in colorectal cancer.

PURPOSE: We studied whether preoperative serum levels of free MMP-2, the MMP-2/TIMP-2 complex, and total amounts of MMP-9, TIMP-1 and TIMP-2 correlated to the tumor stage and prognosis in colorectal cancer. METHODS: Samples from 158 patients operated on for colorectal cancer (100 colon, 58 rectum) and samples from 80 healthy blood donors were analyzed using an ELISA technique. One hundred and thirty-three patients were resected for cure, (31, 61, and 41 in Dukes' stages A, B, and C, respectively). At follow-up in January 1998, 44 patients had died from their cancer after a median time 14 months (range 2-55). Fifteen patients died without tumor relapse. Ninety-nine patients were alive after, a median time of 46 months (range 17-68). RESULTS: Wide, overlapping ranges were observed for all factors both in the patients and in the control group. The patients as compared to the control group had significantly higher levels of free MMP-2 and total amounts of MMP-9, TIMP-1 and TIMP-2, whereas the level of the MMP-2/TIMP-2 complex was significantly lower. TIMP-1 was significantly higher in Dukes' D compared to Dukes' A-C cases; the other factors did not correlate to tumor stage. Elevated TIMP-2 levels (median cut-off limit), only, correlated to worse prognosis when analysed in all patients (p < 0.05). None of the factors (median cut-off limit) correlated to survival in Dukes' A-C patients; analyses based on the upper quartile cut-off limit demonstrated that elevated MMP-2 levels correlated to shorter survival time (p < 0.05). CONCLUSION: Serum analyses of free MMP-2 the MMP-2/TIMP-2 complex and total amounts of MMP-9, TIMP-1 and TIMP-2 are of limited value for tumor staging and prognosis in colorectal cancer.

Adult↗
PubMed2001

[mRNA expression of matrix metalloproteinase-2 and membrane type matrix metalloproteinase in pulmonary fibroblasts and macrophages of rat pulmonary fibrosis model].

OBJECTIVE: To study the changes and significance of MMP-2 and MT1-MMP mRNA expressions in fibroblasts and macrophages of rat pulmonary fibrosis model. METHODS: Fifty pathogen-free Sprague-Dawley rats were randomly divided into ten groups. Five groups were instillated with bleomycin A5 (BLM A5) intratracheally, while 5 control groups with normal saline instead. Pulmonary interstitial fibroblasts and alveolar macrophages were isolated at day 1,3,7,14,28th after BLM exposure. The mRNA expression of MMP-2 and MT1-MMP was evaluated by RT-PCR quantitative analysis. RESULTS: (1) The MMP-2 gene expression of fibroblasts increased 2.05 times(t = 10.667, P < 0.01) higher than that of control in 24 hours after bleomycin instillation and remained at the high level until the 28th day after exposure. It was only slightly increased in macrophages at the first day (t = 3.27, P < 0.05) and dropped down to the level of control during pulmonary fibrosis. (2) The mRNA expressions of MT1-MMP were enhanced both in fibroblasts and macrophages of fibrosis groups. They were 2.1 times(t = 4.823, P < 0.01) higher than that of control at the 14th day and 1.8 times(t = 4.016, P < 0.01) at the 28th day, respectively, in fibroblasts, while it was 2.4 times(t = 5.851, P < 0.01) higher than that of control at the 28th day in macrophages. CONCLUSIONS: (1) Fibroblasts not only were the target cells but also involved in the damage of the pulmonary basement membrane and in the initiation of pulmonary fibrosis mediated by up-regulation of the mRNA expression of MMP-2. (2) The highly expressed MT1-MMP of fibroblasts and macrophages in the late stage of pulmonary fibrosis participated in the activation of pro-MMP-2 to promote the progression of pulmonary fibrosis.

Animals↗
PubMed1996

Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer.

Using quantitative zymography, we measured activity of the type IV collagenases metalloprotease 2 (MMP-2) and MMP-9 in 192 biopsies from colorectal carcinomas, adenomas, and normal bowel. The median level of MMP-9 in samples from Dukes' stage A (n = 18) or C (n = 48) tumors was significantly higher than in stage B carcinomas (n = 65), adenomas (n = 25), and normals (n = 36; P = 0.0001). The median level of active MMP-2 was significantly higher in stage A or C compared with adenomas (P = 0.0001) and normals (P = 0.0001). The median level of inactive MMP-2 was higher in all Dukes' stages compared with normals and adenomas (P = 0.0001). There was a significant increase in inactive MMP-2 from Jass prognostic groups I-IV (P = 0.006) but no correlation with the active enzyme. MMP activity was not related to tumor differentiation, colon versus rectal location, or disease-free, 5-year survival. All groups expressed mRNA for both enzymes, but there were quantitative and locational differences in MMP-2 mRNA expression between normal, benign, and malignant tissues. Thus MMP-2 is controlled at the level of mRNA and protein production and activation in colorectal cancer, and active MMP-2 and MMP-9 enzymes are associated strongly with Dukes' A and C stages of the disease. Variations in MMP levels with the stage or prognostic group of colorectal cancer reflect their differing stromal content.

Adenoma↗
PubMed2001

Regulation of angiogenesis and matrix remodeling by localized, matrix-mediated antisense gene delivery.

Implantation of biomaterials, such as glucose sensors, leads to the formation of a poorly vascularized collagenous capsule that can lead to implant failure. This process, known as the foreign body reaction (FBR), develops in response to almost all biomaterials and consists of overlapping phases similar to those in wound healing. Implantation of porous biomaterials, such as polyvinyl alcohol sponges, also leads to granuloma formation within the interstices of the sponge prior to encapsulation by the FBR. We asked whether delivery of an antisense cDNA for the potent angiogenesis inhibitor thrombospondin (TSP) 2 would enhance blood vessel formation and alter collagen fibrillogenesis in the sponge granuloma and capsule. Collagen solutions were mixed with plasmid to generate gene-activated matrices (GAMs) and applied to biomaterials that were then implanted subcutaneously. Sustained expression of plasmid-encoded proteins was observed at 2 weeks and a month following implantation. In vivo delivery of plasmids, encoding either sense or antisense TSP2 cDNA, altered blood vessel formation and collagen deposition in TSP2-null and wild-type mice, respectively. Untreated implants, implanted next to GAM-treated implants, did not show exogenous gene expression and did not elicit altered responses, suggesting that gene delivery was limited to implant sites. This method of antisense DNA delivery has the potential to improve the performance and life span of implantable delivery devices and biosensors.

Animals↗