Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was to characterise the ability of malignant chondrosarcomas to invade normal bone by analysing their production of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). For this purpose 12 chondrosarcomas were investigated for the expression of mRNAs for several MMPs and all 4 TIMPs by Northern hybridisation, and for immunohistochemical localisation of the proteins. A characteristic finding of these analyses was increased expression of MMP-13, MMP-14 and TIMP-2 mRNAs in chondrosarcomas when compared with nonmalignant control samples. Individual chondrosarcomas also exhibited elevated levels of MMP-1, MMP-7 and MMP-9 mRNAs. The results of Northern hybridisations were supported by immunohistochemical stainings of the corresponding tumour areas for MMP-2, MMP-14 and TIMP-2, further suggesting that these may have prognostic value for determining whether individual chondrosarcomas are locally aggressive or have a probability of recurrence. Another finding of the present study was a marked heterogeneity in histologic appearance and gene expression of the chondrosarcomas, emphasising the importance of analysing several areas of these tumours to get representative results. These findings suggest that analysis of MMPs could be a useful diagnostic indicator in patients with cartilaginous tumours and could help in differentiating between a low-grade malignant chondrosarcoma and a benign growing enchondroma.
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PMID:Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human chondrosarcomas. 1146 3

In view of the essential role of the hemopexin domain of the traditional interstitial collagenases, MMP-1, -8, -13 and MT1-MMP (MMP-14), in determining specific collagen cleavage we have studied the function of this domain in MMP-2, relative to that of the fibronectin-like domain that promotes gelatinolysis. Although the fibronectin-like domain promotes avid binding to collagen, our data demonstrate that the catalytic and hemopexin domains of MMP-2 are sufficient to effect the critical step in cleavage of rat type I collagen into 3/4 and 1/4 fragments. The mechanism of MMP-2 cleavage of collagen proceeds in two phases, the first resembling that of the interstitial collagenases, followed by gelatinolysis, promoted by the fibronectin-like domain.
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PMID:Specific collagenolysis by gelatinase A, MMP-2, is determined by the hemopexin domain and not the fibronectin-like domain. 1151 74

To analyze matrix metalloproteinase (MMP) mRNAs that are expressed in hepatocellular carcinoma cell lines, the kinds of MMP mRNAs were surveyed in HepG2 and Hep3B cells and normal liver by a reverse transcription-polymerase chain reaction using two degenerate primer pairs, derived from conserved domains of known MMPs. The level for each MMP mRNA was examined by Northern blot analysis in HepG2 and Hep3B cells, as well as in normal tissues. It was also examined by a reverse transcription-polymerase chain reaction analysis in 8 different hepatocellular carcinoma cell lines. MMP-2, MMP-14, and MMP-15 mRNAs were expressed at elevated levels in most of the cell lines studied, reflecting that these MMPs would play an important role in the invasion and metastasis of hepatocellular carcinoma. MMP-1, MMP-3, MMP-8, MMP-10, MMP-11, and MMP-13 mRNAs were also expressed in some or most of the cell lines. Interestingly, MMP-9 mRNA, as well as its polypeptide, was undetected in all of the cell lines studied. This implies that MMP-9, which was suggested as a tumor marker for hepatocellular carcinoma, would be expressed in stromal cells, rather than tumor cells. These results provide information for the basal levels of MMP mRNAs in various hepatocellular carcinoma cell lines. It will also facilitate study on the transcriptional regulation of each MMP mRNA by oncogenes.
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PMID:Analysis of matrix metalloproteinase mRNAs expressed in hepatocellular carcinoma cell lines. 1156 28

We describe a new generation of heterocyclic nonpeptide matrix metalloproteinase (MMP) inhibitors derived from a 6H-1,3,4-thiadiazine scaffold. A screening effort was utilized to identify some chiral 6-methyl-1,3,4-thiadiazines that are weak inhibitors of the catalytic domain of human neutrophil collagenase (cdMMP-8). Further optimization of the lead compounds revealed general design principles that involve the placement of a phenyl or thienyl group at position 5 of the thiadiazine ring, to improve unprimed side affinity; the incorporation of an amino group at position 2 of the thiadiazine ring as the chelating agent for the catalytic zinc; the placement of a N-sulfonamide-substituted amino acid residue at the amino group, to improve primed side affinity; and the attachment of diverse functional groups at position 4 or 5 of the phenyl or thienyl group at the unprimed side, to improve selectivity. The new compounds were assayed against eight different matrix metalloproteinases, MMP-1, cdMMP-2, cdMMP-8, MMP-9, cdMMP-12, cdMMP-13, cdMMP-14, and the ectodomain of MMP-14, respectively. A unique combination of the above-described modifications produced the selective inhibitor (2R)-N-[5-(4-bromophenyl)-6H-1,3,4-thiadiazin-2-yl]-2-[(phenylsulfonyl)amino]propanamide with high affinity for MMP-9 (K(i) = 40 nM). X-ray crystallographic data obtained for cdMMP-8 cocrystallized with N-allyl-5-(4-chlorophenyl)-6H-1,3,4-thiadiazin-2-amine hydrobromide gave detailed design information on binding interactions for thiadiazine-based MMP inhibitors.
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PMID:Structure-based design and synthesis of potent matrix metalloproteinase inhibitors derived from a 6H-1,3,4-thiadiazine scaffold. 1156 22

Altered expression of matrix metalloproteases (MMPs) and their inhibitors, the tissue inhibitors of matrix metalloproteases (TIMPs), has been demonstrated in various tumour tissues. mRNA expression patterns of MMP-1, MMP-2, MMP-3, MMP-9, MMP-11, MMP-12, MMP-14 and TIMP-1, TIMP-2, TIMP-3 and TIMP-4 were evaluated by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in 30 renal cell carcinomas (RCC), as well as in the surrounding tissues. Expression of the MMPs was significantly stronger in the carcinomas than in non-malignant tissues. High levels were demonstrated particularly in clear cell RCCs (CC-RCC). Except for MMP-1, MMP expression in the papillary RCCs (P-RCC) was, for most MMPs, significantly lower. Expression of the TIMPs in malignant cells of both subtypes was weak, with the exception of TIMP-4 which was strongly expressed in the P-RCCs and downregulated in the CC-RCCs. The latter was correlated with chromosomal loss of 3p, harbouring the TIMP-4 gene locus. In conclusion, deregulated expression of the MMPs and TIMPs in RCCs differs according to histology, grade, size and cytogenetic characteristics, suggesting that MMP and TIMP expression patterns play an important role for the typical histomorphological features of RCC subtypes and their respective biological behaviour.
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PMID:mRNA expression of matrix metalloproteases and their inhibitors differs in subtypes of renal cell carcinomas. 1157 37

Matrix metalloproteinases (MMPs) are essential in several stages of the metastatic process, and in normal bone development and remodeling. We explored whether the interaction between tumor cells and bone leads to changes in MMP and tissue inhibitor of MMP (TIMP) expression thus affecting osteolysis in metastatic bone disease. Using immunohistochemistry we have investigated the MMP/TIMP expression in tumor cells, fibroblasts, osteoblasts and osteoclasts. Thirty one specimens of bone metastasis from breast carcinoma were stained for MMP-1, -2, -9, MT1-MMP and TIMP-1, and -2 and compared with staining in normal breast tissue, primary breast carcinoma and normal bone. Specimens came from patients in three clinical scenarios: from open biopsies without or with pathological fracture, or bone marrow biopsies containing tumor from patients with pancytopenia but without clinical evidence of osteolysis. By bone histomorphometry the latter group showed a heavy tumor load not different from the open biopsy groups but displayed little active bone resorption and low numbers of osteoclasts. Cell type-specific MMP/TIMP expression was observed and the staining patterns were comparable between the three groups of patients. Though no major differences in the MMP/TIMP staining of tumor cells and fibroblasts were observed between bone metastasis and primary tumor, we showed that tumor cells do express MMPs capable of degrading bone matrix collagen. The number and activity of osteoclasts and osteoblasts was increased dramatically in bone metastases, their MMP/TIMP profiles, however, were not different from normal bone, suggesting that the mechanism of bone degradation by osteoclasts is not different from normal bone remodelling.
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PMID:Immunolocalization of matrix metalloproteinases and their inhibitors in clinical specimens of bone metastasis from breast carcinoma. 1159 3

Cell lines with high metastatic capacity to the lung were established by sequential passage of a human pancreatic cancer cell line (SUIT-2) through the lung of a nude mouse, via the lateral tail vein and from a subcutaneous inoculum. Cells of the parental SUIT-2 and sublines S2-VPx (x-cycle selection from SUIT-2 cells, by Vein-Pulmonary metastasis-culture) and S2-CPx (x-cycle selection, by Cutis-Pulmonary metastasis-culture) were injected intravenously or subcutaneously into nude mice to produce experimental or spontaneous lung metastasis. The S2-VP10 cell line produced pulmonary metastases in 100% of the nude mice, when injected intravenously. It failed, however, to produce more lung colonies than its parent cell line, when injected subcutaneously. The S2-CP8 cell line produced extensive pulmonary metastases in 100% of the nude mice, when injected either intravenously or subcutaneously. This study indicates that the nude mouse provided a good model for in vivo selection of metastatic cells from SUIT-2 cells both experimentally and spontaneously, and that the SUIT-2, S2-VPx, and S2-CPx cell lines will be valuable in the study of human cancer metastasis. We previously reported high levels of ezrin expression in the S2-VP10 and S2-CP8 cell lines. Here we show that these cell lines exhibit a greater capacity to invade or attach to various extracellular matrix components than the parent SUIT-2 cells. The S2-CP8 cell lines also exhibit greater level of type-I and type-IV collagen-degrading activity than the parent SUIT-2 cell line and the S2-VP10 cell line, which shows similar collagen-degrading activity to the parent SUIT-2 cells. In RT-PCR studies, SUIT-2, S2-CP8 and S2-VP10 cell lines constitutively expressed many matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP7, MMP-9, MMP-10 and MMP-14). These results suggest that some parameters that enhance adhesion and invasion are important to both experimental and spontaneous metastasis and the collagen degrading enzymes are predicted to play a key-role during spontaneous metastasis.
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PMID:High collagenolytic activity in spontaneously highly metastatic variants derived from a human pancreatic cancer cell line (SUIT-2) in nude mice. 1168 61

The aim of the work was to analyze, on a comparative basis, the signaling pathways operating in the regulation of a panel of matrix metalloproteinases (MMP) expressed by human dermal fibroblasts submitted to mechanical stress relaxation by cytochalasin D (CD) and in a retracting collagen gel (RCG). The mRNA steady-state level of MMPs was measured by a quantitative RT-PCR procedure using a synthetic RNA as internal standard. In monolayer, most MMPs were barely detected, except MMP-2. Disruption of the actin stress fibers by CD induced a moderate increase of MMP-2 mRNA and a much larger stimulation of MMP-3, -9, -13 and -14 mRNAs. In RCG, a significant up-regulation of these MMPs was also observed although to a lower extent than in CD-treated monolayers. Among the investigated MMPs, the MMP-8 and -11 were not reproducibly detected. MMP-2 was processed to its active form both by CD and in RCG. The CD-induced up-regulation of gene expression was largely repressed by blocking protein synthesis by cycloheximide for all the MMPs, by inhibiting the tyrosine-kinases of the src family by herbimycin A for all MMPs, except MMP-2, and by inhibiting the TPA-inducible PKC isoforms by bisindoyl maleimide for all MMPs, except MMP-14. The up-regulation induced by stress relaxation in RCG was protein synthesis-dependent for MMP-2 and MMP-13, tyrosine kinases-dependent for MMP-3 and MMP-13, as previously described for MMP-1. Inhibiting TPA-inducible PKC did not affect any MMP in RCG except MMP-13, which was strongly induced. The processing of MMP-2 was tyrosine kinases-dependent but PKC-independent. Inhibitors of the ERK1,2 and p38 MAP kinases pathways diversely affected the MMPs expression. Inhibiting the Rho-kinase activity by Y-27632 was inactive. These results point to the potent regulation operated by the status of the cytoskeleton on the cell phenotype, and to distinct regulatory pathways involved in the control of different MMPs expression.
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PMID:Distinct pathways in the over-expression of matrix metalloproteinases in human fibroblasts by relaxation of mechanical tension. 1169 80

BMS-275291 is an p.o. bioavailable, sulfhydryl-based matrix metalloproteinase (MMP) inhibitor currently in clinical development for the treatment of cancer. This inhibitor was designed to potently inhibit MMP activities while minimally affecting those of other metalloproteases (e.g., sheddases) involved in the release of cell-associated molecules such as tumor necrosis factor-alpha, tumor necrosis factor-alpha receptor, interleukin-6 receptor, or L-selectin. In vitro, BMS-275291 is a potent inhibitor (nM) of the activities of MMP-1, MMP-2, MMP-7, MMP-9, and MMP-14. BMS-275291 inhibits tumor growth in a B16BL6 model of experimental metastasis, and in this model, BMS-275291 treatment results in a dose-dependent reduction in the number of lung metastases compared with vehicle controls. BMS-275291 also inhibits angiogenesis in a murine angiogenesis model, where once daily treatment with BMS-275291 results in a dose-dependent inhibition of endothelial cell migration into s.c. implanted Matrigel plugs. Pharmacokinetic studies demonstrated that the plasma concentrations of parent BMS-275291 in mice exceeds the in vitro IC(50) values for MMP-1, MMP-2, MMP-7, MMP-9, and MMP-14 for at least 4 h after the administration of a therapeutic dose of BMS-275291. Taken together, these data demonstrate that BMS-275291 inhibits MMP activities that contribute to tumor metastasis and angiogenesis.
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PMID:Inhibition of angiogenesis and metastasis in two murine models by the matrix metalloproteinase inhibitor, BMS-275291. 1173 31

The thinning of the cornea that occurs in keratoconus has been well described; however, the mechanism of tissue degradation remains unknown. Elevated proteinase activity is one possibility and approximately 20 publications over the last 20 years have addressed this hypothesis. Early studies reported increased collagenase and gelatinase activities in the medium of keratoconus corneal cultures. After the characterization of the matrix metalloproteinase (MMP) enzymes, studies focused on the expression of specific MMPs, in particular the gelatinases, MMP-2 and MMP-9. Matrix metalloproteinase-2 was found to be the major MMP of the cornea and was constitutively produced in normal tissue, whereas MMP-9 expression was induced by various stimuli, including phorbol esters and even tissue culturing. These studies suggested that there were no differences in the amounts or states of activation of MMP between normal and keratoconus corneas, although the amounts of some proteinase inhibitors, including tissue inhibitors of metalloproteinases, alpha-1-proteinase inhibitor and alpha-2-macroglobulin, were decreased in keratoconus. Most recently, the lysosomal proteinases, cathepsin B and cathepsin G were reported to be elevated in keratoconus corneas, and it is possible that it was cathepsin activity, not MMP activity, that was measured in some early studies. Nevertheless, there are now about 20 human MMPs identified and it is possible that some of these, other than the well known collagenase (MMP-1) and gelatinases (MMP-2 and MMP-9), could be implicated in the pathology of keratoconus. Studies have begun to address more recently described MMPs and it has been reported that the membrane-bound MT1-MMP (MMP-14), which activates latent MMP-2, was found to have increased expression in keratoconus corneas, whereas the stromelysins, MMP-3 and MMP-10, were not.
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PMID:Is the corneal degradation in keratoconus caused by matrix-metalloproteinases? 1177


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