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At least 1,045 records · Page 58Linked to original sources
PubMed2002

A single nucleotide polymorphism in the matrix metalloproteinase-3 promoter enhances breast cancer susceptibility.

PURPOSE: Matrix metalloproteinases (MMPs) are likely to be involved in invasion and metastasis of several tumors by degrading the extracellular matrix. A single adenine insertion/deletion polymorphism (5A/6A) in the MMP-3 promoter region causes the elevation of transcriptional level and local expression of MMP-3. The aim of this pilot study was to evaluate the impact of this 5A/6A polymorphism on susceptibility and metastasis in breast cancer. EXPERIMENTAL DESIGN: Genotyping for 5A/6A polymorphism was performed in 86 Italian women operated on for breast cancer and followed for 6-30 months (median follow-up, 21 months). A control population of 110 Italian age-matched tumor-free women was also genotyped for the same polymorphism. The 1G/2G gene promoter polymorphism for MMP-1 was additionally tested. RESULTS: The frequency of 5A allele was higher in the breast cancer group than in controls (P = 0.035; odds ratio, 1.53; 95% confidence interval, 1.02-2.29). The breast cancer group was divided into a group without metastasis (M-) and a group that had developed metastasis (M+). At the time of diagnosis, the 5A allele was more prevalent in the M+ group than in controls (P = 0.010; odds ratio, 1.96; 95% confidence interval, 1.16-3.30). The difference between M- patients and controls did not reach statistical significance (P = 0.37). This study was not able to demonstrate any statistical differences with respect to 1G/2G polymorphism between controls and cases and between M+ and M- subgroups. CONCLUSIONS: Although this should be considered only as a pilot study, our results suggest that the presence of 5A polymorphism at the MMP-3 promoter region may represent an unfavorable prognostic feature in breast cancer patients associated with more invasive disease.

Adenocarcinoma↗
PubMed2003

The expression of novel membrane-type matrix metalloproteinase isoforms is required for normal development of zebrafish embryos.

Matrix metalloproteinases (MMPs) play important roles in the turnover of components of extracellular matrix (ECM) and in the processing of active and latent-signaling molecules bound to the ECM or associated with the cell surface. Through such actions, MMPs regulate a variety of cellular and developmental processes. Membrane-type matrix metalloproteinases (MT-MMPs) are of particular importance because they function in the immediate pericellular environment that modulates both cell-cell and cell-ECM interactions. In this study, we utilized zebrafish as a developmental model to study the role of MT-MMPs during early embryogenesis. We successfully isolated two isoforms of a MT-MMP homologue that are structurally similar to MT1-MMP. They have been named zebrafish MT-MMPalpha and beta. Zebrafish MT-MMPbeta is unique among vertebrate MT-MMPs in that it contains an Arg-Glu-Asp (RED) multiple-repeat motif in its linker region. Whole mount in situ analysis, RT-PCR, immunofluorescence, reporter analysis, Western blot analysis, and zymography indicated that MT-MMPalpha and beta were expressed through at least the first 72 h of development and that this expression was targeted to the cell surface. Functional studies using injection of either mRNA or morpholino antisense oligonucleotides resulted in a truncation of the cranial to caudal axis as monitored through 72 h post fertilization, indicating that zebrafish MT-MMPalpha and beta had an important role in embryonic development. Axis markers indicated that these effects likely involved processes occurring later than 10 h of embryogenesis.

Amino Acid Sequence↗
PubMed2003

Differential activity of the gelatinases (matrix metalloproteinases 2 and 9) in the fetal membranes and decidua, associated with labour.

Degradation of the extracellular matrix in fetal membranes has been implicated in the rupture of fetal membranes, the process of parturition and placental detachment from the decidua after parturition. In this study we assessed labour-associated changes in gelatinase activity in cultured human amnion, chorion and decidua, as well as in amniotic fluid. We found that in media conditioned by decidua, following the establishment of uterine contractions, matrix metalloproteinase-2 (MMP-2) activity is increased while the protein tissue inhibitors of matrix metalloproteinase-1 (TIMP-1) level is decreased. The formation of a 130 kDa gelatinase band was also significantly increased after contractions began. In media conditioned by chorion, the initiation of uterine contractions did not change MMP activity or TIMP-1 levels. However, an increase in MMP-9 activity and a decrease in TIMP-1 protein levels were observed following the establishment of uterine contractions in media conditioned by amnion. We suggest that this differential spatial regulation provides a form for modulatory hieratical activity of the MMPs in the onset of labour allowing rupture of the membranes while avoiding premature placental separation.

Decidua↗
PubMed2000

Differential regulation of three thyroid hormone-responsive matrix metalloproteinase genes implicates distinct functions during frog embryogenesis.

Matrix metalloproteinases (MMPs) are a family of Zn(2+)-dependent extracellular proteases capable of degrading various proteinaceous components of the extracellular matrix (ECM). They are expressed in developmental and pathological processes such as postlactation mammary gland involution and tumor metastasis. Relatively few studies have been carried out to investigate the function of MMPs during embryogenesis and postembryonic organ development. Using Xenopus development as a model system, we and others have previously isolated three MMP genes as thyroid hormone response genes. They have distinct temporal and organ-specific regulations during thyroid hormone-dependent metamorphosis. We demonstrate here that three MMPs-stromelysin-3 (ST3), collagenases-3 (Col3), and collagenases-4 (Col4)-also have distinct spatial and temporal expression profiles during embryogenesis. Consistent with earlier suggestions that ST3 is a direct thyroid hormone response gene whereas Col3 and Col4 are not, we show that precocious overexpression of thyroid hormone receptors in the presence of thyroid hormone lead to increased expression of ST3, but not Col3. Furthermore, our whole-mount in situ hybridizations reveal a tight but distinct association of individual MMPs with tissue remodeling in different regions of the animal during embryogenesis. These results suggest that ST3 is likely to play a role in ECM remodeling that facilitate apoptotic tissue remodeling or resorption, whereas Col3 and Col4 appear to participate in connective tissue degradation during development.

Animals↗
PubMed2003

Cross-talk between RhoGTPases and stress activated kinases for matrix metalloproteinase-9 induction in response to keratinocytes injury.

Cell migration and extracellular matrix remodeling are two essential processes of wound healing, regulated by extracellular metalloproteinases such as matrix metalloproteinase-2 (Gelatinase A) and matrix metalloproteinase-9 (Gelatinase B). Expression of matrix metalloproteinase-9 is deregulated in numerous wound healing pathologies. To date the mechanisms regulating matrix metalloproteinase-9 during normal wound healing are poorly documented. Using both primary cultures of normal human keratinocytes and a wounding device especially designed to dissect the molecular events during the healing process in vitro, we show that matrix metalloproteinase-9 is stimulated by injury in normal human keratinocytes. This upregulation results from the mechanical stress created by injury and not from a soluble factor, secreted by wounded normal human keratinocytes. We also demonstrate that the Rho family of small GTPases, p38[MAPK] and JNK together play a key part in the signaling pathways controlling the stimulation of matrix metalloproteinase-9 in wounded cells. We provide lines of evidence indicating that in wounded keratinocytes, upregulation of matrix metalloproteinase-9 depends on two distinct pathways. The first involves Rac1 and/or Cdc42 that control the activation of p38[MAPK]. The second depends on RhoA activation that is required for stimulation of JNK.

Gene Expression Regulation↗
PubMed2004

Expression of matrix metalloproteinases in feline vaccine site-associated sarcomas.

OBJECTIVES: To screen for expression of 9 predominant members of the matrix metalloproteinase (MMP) family, including membrane-type matrix metalloproteinases (MT-MMPs) and tissue inhibitors of metalloproteinases (TIMPs), in primary tumor tissue biopsy specimens of vaccine site-associated sarcomas (VSS) in cats and compare expression profiles of VSS with expression profiles of non-VSS and carcinomas. SAMPLE POPULATION: 31 primary tumor tissue biopsy specimens and 6 nontumor (normal) tissue biopsy specimens. PROCEDURES: Tissue specimens were obtained from primary tumor biopsy specimens of cats. Primers for reverse transcriptase-polymerase chain reaction assay were designed on the basis of known sequences. Data were analyzed for patterns of expression of MMPs, MT-MMPs, and TIMPs. Differences in expression patterns were evaluated among cats of differing genders, ages, metastasis status, and overall survival durations, and between cats with VSS and cats with non-VSS tumor types. RESULTS: A total of 31 primary tumor tissue biopsy specimens and 6 nontumor (normal) tissue biopsy specimens were screened for the presence of 6 MMPs and 3 TIMPs. Matrix metalloproteinase and TIMP expression was found in non-VSS, carcinomas, and VSS. No significant differences were found in patterns of expression among tumor types. Metastasis was found to be the only predictive factor for overall survival duration. A significant correlation was found between MMP2 and MT-MMP16 expression and overall duration of survival. CONCLUSIONS AND CLINICAL RELEVANCE: The identification of MMPs in feline VSS supports an underlying inflammatory pathogenesis for this tumor. Expression of MMP2 and MT-MMP16 were correlated with survival time in our study.

Analysis of Variance↗
PubMed1997

Suppression of matrix metalloproteinases inhibits establishment of ectopic lesions by human endometrium in nude mice.

Matrix metalloproteinases of the stromelysin family are expressed in the human endometrium as a consequence of cellular events during the menstrual cycle that require extracellular matrix remodeling. We have recently documented the presence of these enzymes in lesions of endometriosis, a benign disease that presents as persistent ectopic sites of endometrial tissue, usually within the peritoneal cavity. Endometriosis can develop after retrograde menstruation of endometrial tissue fragments, and establishment of ectopic sites within the peritoneal cavity requires breakdown of extracellular matrix. To examine whether matrix metalloproteinases might contribute to the steroid-dependent epidemiology and cellular pathophysiology of endometriosis, we have developed an experimental model of endometriosis using athymic nude mice as recipients of human endometrial tissue. Our results demonstrate that estrogen treatment of human endometrial tissue in organ culture maintains secretion of matrix metalloproteinases, and promotes establishment of ectopic peritoneal lesions when injected into recipient animals. In contrast, suppressing metalloproteinase secretion in vitro with progesterone treatment, or blocking enzyme activity with a natural inhibitor of metalloproteinases, inhibits the formation of ectopic lesions in this experimental model.

Adult↗
PubMed2002

Matrix metalloproteinases and their inhibitors in bone remodelling following distraction osteogenesis of the sheep mandible.

AIM: Matrix metalloproteinases (MMPs), together with their tissue inhibitors (TIMPs), are responsible for the controlled degradation of collagen and other matrix substrates in bone and other tissues. This study evaluated the expression of MMPs and TIMPs in bony remodelling in a bilateral sheep mandible model up to 12 months following lengthening by distraction osteogenesis. METHODOLOGY: Sheep mandibles were harvested 3, 6, 9 or 12 months following lengthening by bilateral mandibular distraction (1 mm/day for 20 days). Undistracted sheep mandibles were used as controls. The tissues underwent routine histology and immunohistochemical staining with monoclonal antibodies specific to MMPs 1-3 and TIMP-1, 2. Matrix and cell staining was assessed using a semi-quantitative analysis. RESULTS: Matrix metalloproteinases and their tissue inhibitors (TIMPs) expression levels were marked at 3 months and decreased thereafter becoming similar to undistracted controls by 12 months. The histologic development of mature lamellar cortical bone was similar to undistracted controls by 9 months following distraction. CONCLUSIONS: A temporal expression of MMPs and TIMPs was found in distraction osteogenesis. MMPs and TIMPS may, in part, reflect the state of bony remodelling following mandibular lengthening by distraction osteogenesis. Matrix metalloproteinases and TIMP expression were comparable to undistracted controls by 12 months, suggesting that equilibrium had been achieved and that bony relapse is unlikely.

Animals↗
PubMedDate not supplied

In vitro and in vivo inhibition of skin matrix metalloproteinases by Pothomorphe umbellata root extract.

Exposure to UV radiation up-regulates the synthesis of matrix metalloproteinases (MMPs), a group of matrix-degrading enzymes. MMPs are regarded as promising therapeutic targets and the development of effective inhibitors is an important research focus. The plant Pothomorphe umbellata has been shown to exert a potent antioxidant activity on the skin and to delay the onset and reduce the incidence of UVB-induced chronic skin damage. The aim of the present study was to determine the effect of P. umbellata ethanolic root extract on MMP-2 and MMP-9. The in vitro inhibition of MMP-2 and MMP-9 was measured by gelatin zymography in the presence of different concentrations of P. umbellata extract, as well as in the presence of its isolated active principle 4-nerolidylcatechol (4-NC). The inhibitory effect of the P. umbellata extract was stronger than that of 4-NC. Gelatin zymography and histological analysis revealed that P. umbellata was able to inhibit constitutive MMP-9 activity in vivo in mice sacrificed 2 h after UVB irradiation. The intensity of the MMP-2 band was unchanged. Our data contribute to the elucidation of the mechanism of prevention of photoaging by P. umbellata and may provide a rational basis for the use of this plant in prophylaxis against and treatment of skin cancer.

Animals↗
PubMed2002

The role of matrix metalloproteinase polymorphisms in the rate of decline in lung function.

The matrix metalloproteinases (MMPs) comprise a family of at least 20 proteolytic enzymes that play an essential role in tissue remodeling. MMP1 (interstitial collagenase), MMP9 (gelatinase B) and MMP12 (macrophage elastase) are thought to be important in the development of emphysema. A number of naturally occurring polymorphisms of human MMP gene promoters have been identified and found to alter transcriptional activity. Additionally, we detected a novel polymorphism in the MMP12 coding region (Asn357Ser). The aim of this study was to investigate the role of MMP polymorphisms in the development of chronic obstructive lung disease. We determined the prevalence of these polymorphisms in 590 continuing smokers chosen from the National Heart Lung and Blood Institute, Lung Health Study for having the fastest (n = 284) and slowest (n = 306) 5 year rate of decline of lung function. Of the five polymorphisms, only G-1607GG was associated with a rate of decline in lung function. The -1607GG allele was associated with a fast rate of decline (P = 0.02) [corrected]. However, haplotypes consisting of alleles from the MMP1 G-1607GG and MMP12 Asn357Ser polymorphisms were associated with rate of decline of lung function (P = 0.0007). These data suggest that polymorphisms in the MMP1 and MMP12 genes, but not MMP9, are either causative factors in smoking-related lung injury or are in linkage disequilibrium with causative polymorphisms.

Base Sequence↗
PubMed2003

Extracellular matrix and matrix metalloproteinases in sciatic nerve.

Although matrix metalloproteinases (MMPs) are increasingly being implicated in several pathologies of the nervous system, it is not yet clear what role they play in normal neurobiological processes. We review the expression of extracellular matrix (ECM) components as well as MMPs and tissue inhibitors of metalloproteinases (TIMPs) in the peripheral nervous system. We explore the expression of certain MMPs and the four TIMPs at the mRNA level in the postnatal mouse sciatic nerve. In addition, we have used substrate gel and in situ zymography to determine levels of MMP-2 and -9 and TIMP activity in rat sciatic nerve after crush and during regeneration. A rapid and transient increase in MMP-9 localised at and immediately distal to the site of injury was observed, whereas an increase in MMP-2 activity was delayed, prolonged, and extended proximal and distal to the injury site. This activity coincides with periods of axonal elongation, suggesting that it could act to facilitate axonal extension along the nerve matrix. We also detected multiple species of gelatinolytic inhibitory activity, including TIMP-1 and -3 in control and injured nerve. These activities probably act to prevent uncontrolled gelatinolytic activity, maintaining nerve integrity at the level essential for axonal regrowth.

Animals↗
PubMed1998

Induction of matrix metalloproteinase expression in human macrophages by orthopaedic particulate debris in vitro.

We exposed human macrophages isolated from the peripheral blood of healthy donors to metal and bone-cement particles from 0.2 to 10 microm in size. Zymography showed that macrophages exposed to titanium alloy and polymethylmethacrylate (PMMA) particles released a 92- and 72-kDa gelatinase in a dose- and time-dependent manner. Western immunoblotting confirmed that the 92- and 72-kDa gelatinolytic activities corresponded to matrix metalloproteinase-9 and matrix metalloproteinase-2 (MMP-9, MMP-2), respectively. Western immunoblotting also indicated that titanium alloy and PMMA particles increased the release of MMP-1. Northern blotting showed elevated mRNA signal levels for MMP-1, MMP-2, and MMP-9 after exposure to both types of particle. Collagenolytic activity also increased in the macrophage culture medium in response to both types of particle. Our findings support the hypothesis that macrophages release MMPs in proportion to the amount of particulate debris within periprosthetic tissues.

Alloys↗
PubMed2001

The role of matrix metalloproteinases in tumor invasion, metastasis, and angiogenesis.

Tumor invasion and metastasis formation are the hallmarks of malignant cancer. Metastatic spread of cancer cells is a result of a complex cascade of cellular events. This article discusses the matrix metalloproteinase family, the regulation of matrix metalloproteinase activity, and the functions of matrix metalloproteinases in tumor progression.

Disease Progression↗
PubMed1992

The small matrix metalloproteinase of the rat uterus.

The uterus of the rat contains a small metalloproteinase that digests Azocoll and proteoglycan. The activity of this enzyme is elevated in the postpartum uterus and parallels the rate of breakdown of matrix proteoglycan (Sellers, A. and Woessner, J.F., Jr., Biochem. J. 189: 521, 1980). The enzyme has been purified to homogeneity. Its molecular weight is 28,000 for the latent form of the enzyme and 19,000 for the active form, as determined by SDS/PAGE. The enzyme has no action on collagens of type I, III, IV or V, but it does digest gelatins of these 4 types. Digestion of type I gelatin is most pronounced for the alpha-2 chain, which is cleaved to two major bands. The B chain of insulin is cleaved at Ala14-Leu15 and Tyr16-Leu17. Proteoglycan is degraded, but no action can be detected against elastin. Both zinc and calcium ions are required for activity. Low levels of phosphoramidon or Zincov are not inhibitory. Detailed comparisons with human gelatinase (matrix metalloproteinase 2) and stromelysin (matrix metalloproteinase 3) show that the uterine proteinase has a distinctive pattern of specificity. The properties match those of human Pump-1 as reported by Quantin et al., Biochemistry 28: 5327, 1989. It is proposed to designate this proteinase as matrix metalloproteinase 7.

Animals↗
PubMed1993

Role of matrix metalloproteinases in human periodontal diseases.

Matrix metalloproteinases (MMP) are a family of proteolytic enzymes that mediate the degradation of extracellular matrix macromolecules, including interstitial and basement membrane collagens, fibronectin, laminin, and proteoglycan core protein. The enzymes are secreted or released in latent form and become activated in the pericellular environment by disruption of a Zn(++)-cysteine bond which blocks the reactivity of the active site. The major cell types in inflamed and healthy periodontal tissues (fibroblasts, keratinocytes, endothelial cells, and macrophages) are capable of responding to growth factors and cytokines, as well as to products released from the microbial flora by induction of transcription of 1 or more MMP genes. Cytokines that are likely to regulate expression of MMP genes in periodontal tissues include IL-1, TNF-alpha, and TGF-alpha. In addition, triggered PMN leukocytes which express only 2 MMP (PMN-CL and Mr 92K GL) release these enzymes from specific granule storage sites in response to a number of stimuli. The evidence that MMP are involved in tissue destruction in human periodontal diseases is still indirect and circumstantial. Cells isolated from normal and inflamed gingiva are capable of expressing a wide complement of MMP in culture and several MMP can be detected in cells of human gingiva in vivo. In addition, PMN-CL and Mr 92K GL are readily detected in gingival crevicular fluid from gingivitis and periodontitis patients. Osteoclastic bone resorption does not appear to directly involve MMP, but a body of evidence suggests that bone resorption is initiated by removal of the osteoid layer by osteoblasts by means of a collagenase-dependent process.

Extracellular Matrix↗
PubMed1995

Steps involved in activation of the pro-matrix metalloproteinase 9 (progelatinase B)-tissue inhibitor of metalloproteinases-1 complex by 4-aminophenylmercuric acetate and proteinases.

The precursor of matrix metalloproteinase 9 (pro-MMP-9, progelatinase B) noncovalently binds to tissue inhibitor of metalloproteinases (TIMP)-1 through the C-terminal domain of each molecule. We have isolated the proMMP-9.TIMP-1 complex from the medium of human fibrosarcoma HT-1080 cells and investigated the activation processes of the complex by 4-aminophenylmercuric acetate, trypsin, and matrix metalloproteinase 3 (MMP-3, stromelysin 1). The treatment of the proMMP-9.TIMP-1 complex with 4-aminophenylmercuric acetate or trypsin converts proMMP-9 to lower molecular weight species corresponding to active forms, but no gelatinolytic activity is detected. The lack of enzymic activity results from binding of TIMP-1 to the activated MMP-9. The treatment of the proMMP-9.TIMP-1 complex with a possible physiological proMMP-9 activator, MMP-3, does not reveal any gelatinolytic activity unless the molar ratio of MMP-3 to the complex exceeds 1. This is due to the inhibition of MMP-3 by TIMP-1 forming a ternary proMMP-9.TIMP-1.MMP-3 complex. The formation of the ternary complex weakens the interaction between proMMP-9 and TIMP-1, resulting in partial dissociation of the complex into proMMP-9 and the TIMP-1.MMP-3 complex. When MMP-3 is in excess, the propeptide is completely processed, and the full activity of MMP-9 is detected. Similarly, the proMMP-9.TIMP-1 complex inhibits MMP-1 (interstitial collagenase) and in turn renders the proMMP-9 activable by a catalytic amount of MMP-3. These results suggest that formation of the proMMP-9.TIMP-1 complex regulates extracellular matrix breakdown in tissue by switching the predominant MMP activity from one type to another.

Collagenases↗
PubMed2006

[Effects of salidroside on bone marrow matrix metalloproteinases of bone marrow depressed anemic mice].

To examine the effect of salidroside on the expression and activities of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in bone marrow (BM) of BM depressed anemic mice by immunohistochemistry and gelatin zymography respectively, and to explore its roles in hematopoietic regulation. Immunohistochemistry showed that the expression of MMP-2 and MMP-9 of bone marrow cells (BMCs) was found in each group. Compared with control group, the expression of MMP-2 and MMP-9 was obviously increased in the model group, low-dose, middle-dose and high-dose salidroside. At day 4 after treatment of radiation and chemotherapy, the peak of the expression of MMP-2 and MMP-9 was found in middle-dose salidroside . At day 8 after treatment of radiation and chemotherapy, the peak of the expression of MMP-2 and MMP-9 was found in low-dose and middle-dose salidroside respectively. Gelatin zymography revealed that 66 kD proMMP-2, 62 kD MMP-2, 86 kD MMP-9 and 94 kD proMMP-9 were detected in control group, and the activity of MMP-9 was stronger among them. After treatment of radiation and chemotherapy, the activity of gelatinases of hemopoietic microenviroment (HM) was obviously decreased, but low-dose, middle-dose and high-dose salidroside could significantly increase the activities of proMMP-9 and MMP-9, attenuate the activity of proMMP-2. These results suggest that salidroside could promote the recovery of hematopoietic function of BM depressed anemic mice by increasing the expression and activity of MMPs, releasing the cytokines from ECM or cell membrane, repairing impaired microvessels of HM and promotion proliferation, migration and differentiation of HSCs.

Anemia, Aplastic↗
PubMed2003

Roles of matrix metalloproteinases in tumor metastasis and angiogenesis.

Matrix metalloproteinases (MMPs), zinc dependent proteolytic enzymes, cleave extracellular matrix (ECM: collagen, laminin, firbronectin, etc) as well as non-matrix substrates (growth factors, cell surface receptors, etc). The deregulation of MMPs is involved in many diseases, such as tumor metastasis, rheumatoid arthritis, and periodontal disease. Metastasis is the major cause of death among cancer patients. In this review, we will focus on the roles of MMPs in tumor metastasis. The process of metastasis involves a cascade of linked, sequential steps that involve multiple host-tumor interactions. Specifically, MMPs are involved in many steps of tumor metastasis. These include tumor invasion, migration, host immune escape, extravasation, angiogenesis, and tumor growth. Therefore, without MMPs, the tumor cell cannot perform successful metastasis. The activities of MMPs are tightly regulated at the gene transcription levels, zymogen activation by proteolysis, and inhibition of active forms by endogenous inhibitors, tissue inhibitor of metalloproteinase (TIMP), and RECK. The detailed regulations of MMPs are described in this review.

Animals↗