Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mammary gland develops its adult form by a process referred to as branching morphogenesis. Many factors have been reported to affect this process. We have used cultured primary mammary epithelial organoids and mammary epithelial cell lines in three-dimensional collagen gels to elucidate which growth factors, matrix metalloproteinases (MMPs) and mammary morphogens interact in branching morphogenesis. Branching stimulated by stromal fibroblasts, epidermal growth factor, fibroblast growth factor 7, fibroblast growth factor 2 and hepatocyte growth factor was strongly reduced by inhibitors of MMPs, indicating the requirement of MMPs for three-dimensional growth involved in morphogenesis. Recombinant stromelysin 1/MMP3 alone was sufficient to drive branching in the absence of growth factors in the organoids. Plasmin also stimulated branching; however, plasmin-dependent branching was abolished by both inhibitors of plasmin and MMPs, suggesting that plasmin activates MMPs. To differentiate between signals for proliferation and morphogenesis, we used a cloned mammary epithelial cell line that lacks epimorphin, an essential mammary morphogen. Both epimorphin and MMPs were required for morphogenesis, but neither was required for epithelial cell proliferation. These results provide direct evidence for a crucial role of MMPs in branching in mammary epithelium and suggest that, in addition to epimorphin, MMP activity is a minimum requirement for branching morphogenesis in the mammary gland.
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PMID:The interplay of matrix metalloproteinases, morphogens and growth factors is necessary for branching of mammary epithelial cells. 1168 61

Oral squamous cell carcinoma (SCC) is characterized by invasive growth and the propensity for distant metastasis. The expression of specific adhesion receptors promotes defined interactions with the specific components found within the extracellular matrix (ECM). We previously showed that the alpha v beta 6 fibronectin receptor is highly expressed in oral SCC. Here we forced expression of the beta 6 subunit into poorly invasive SCC9 cells to establish the SCC9 beta 6 cell line and compared these two cell lines in several independent assays. Whereas adhesion to fibronectin was unaffected by the expression of beta 6, migration on fibronectin and invasion through a reconstituted basement membrane (RBM) were both increased. Function-blocking antibodies to alpha v beta 6 (10D5) reduced both migration on fibronectin and invasion through an RBM, whereas anti-alpha 5 antibodies were effective only in suppressing migration on fibronectin, not invasion. Expression of beta 6 also promoted tumor growth and invasion in vivo and modulated fibronectin matrix deposition. When grown as a co-culture with SCC9 cells, peritumor fibroblasts (PTF) organized a dense fibronectin matrix. However, fibronectin matrix assembly was decreased in co-cultures of SCC9 beta 6 cells and PTF and this decrease was reversed by the addition of function-blocking anti-alpha v beta 6 antibodies. The expression of beta 6 also resulted in increased levels of matrix metalloproteinase 3. Addition of the general MMP inhibitor GM6001 to SCC9 beta 6/PTF co-cultures dramatically increased fibronectin matrix assembly in a similar fashion as incubation with anti-alpha v beta 6 antibodies. These results demonstrate that expression of beta 6 (1) increases oral SCC cell motility and growth in vitro and in vivo; (2) negatively affects fibronectin matrix assembly; and (3) stimulates the expression and activation of MMP3. We suggest that the integrin alpha v beta 6 is a key component of oral SCC invasion and metastasis through modulation of MMP-3 activity.
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PMID:Expression of integrin beta 6 enhances invasive behavior in oral squamous cell carcinoma. 1200 35

Smoking is a major risk factor for coronary heart disease (CHD), but this risk may be modified by an individual's genotype. A common functional 5A/6A polymorphism in the promoter of the stromelysin-1 (matrix metalloproteinase 3, MMP3) gene has been identified. The 6A allele has been consistently associated with faster progression of angiographically determined CHD, while the 5A allele has recently been associated with risk of acute myocardial infarction (MI) in patients with unstable angina. To date there has been no prospective study of the relationship of this genotype to CHD risk in smokers and non-smokers. DNA was available from 2,743 middle-aged men, free of CHD at baseline, recruited through nine general practices in the UK for prospective surveillance. To date there have been almost 24,000 person-years of follow-up with 125 CHD events (fatal and non-fatal MI, sudden coronary death, need for coronary artery surgery or new major ECG Q-wave abnormality). Men with events were each matched for age, practice and cholesterol level with three healthy men. Smoking habit was determined by questionnaire. 5A/6A genotype was determined using a heteroduplex generator method. Associations between genotype and disease outcome, according to smoking status, were assessed using conditional logistic regression. Overall, current smoking was associated with a relative risk (RR) of 1.99 (95% CI 1.30-3.06) as compared with never-smokers and ex-smokers combined (p&0.002). In non-smoking men, and after adjustment for conventional risk factors, compared with the 5A5A group, the RR was 1.37 (0.64-2.94) in those with the genotype 5A6A and 3.02 (1.38-6.61) in those with the genotype 6A6A. Smoking increased risk 1.4 fold in the 5A6A group to 1.91 (1.84-4.36), by 1.3 fold in the 6A6A group to 4.01 (1.57-10.24), but by 3.81 fold (1.54-9.40) in the 5A5A group (smoking-genotype interaction p = 0.01). The data indicate a key role for stromelysin in the atherosclerotic process. Men with the stromelysin genotype 5A5A represent 29% of the general population, and their high risk, if smokers, provides a further strong argument for smoking avoidance.
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PMID:Interaction between smoking and the stromelysin-1 (MMP3) gene 5A/6A promoter polymorphism and risk of coronary heart disease in healthy men. 1248 68

The genetic background of rheumatoid arthritis (RA) is only partly understood, and several genes seem to be involved. The matrix metalloproteinases MMP1 (interstitial collagenase) and MMP3 (stromelysin 1) are thought to be important in destructive joint changes seen in RA. In the present study, functional relevant promoter polymorphisms of MMP1 and MMP3 were genotyped in 308 patients and in 110 controls, to test whether the polymorphisms contribute to the severity of the disease measured by radiographic progression of joint destruction. For comparison, the shared epitope of HLA DR4 and DR1 (SE) was determined by polymerase chain reaction. There was no association of MMP polymorphisms with susceptibility to RA. However, a strong linkage disequilibrium was observed between the 1G/2G (MMP1) and the 5A/6A (MMP3) polymorphisms (P << 10(-6); linkage disequilibrium index D' = 0.46). In factorial regression, the degree of radiographic joint destruction correlated significantly with the 1G-5A haplotype (P = 0.0001) and the interaction term 'estimated number of 1G-5A haplotypes x duration of disease' (P = 0.0007). This association was phasic, indicating that possession of the 1G-5A haplotype has a protective effect over a period of about 15 years of RA, but might be associated with a more pronounced radiographic progression later on. Similar results were also found with the 1G allele of MMP1 alone (P = 0.015) and with the interaction term 'estimated number of 1G alleles x duration of disease' (P = 0.014). The correlation of SE with the Ratingen score was comparable (0.044). The regression model of MMP haplotypes explained 35% of the variance of the radiographic score, whereas the SE explained 29%. The 1G-5A haplotype across the closely linked MMP1 and MMP3 gene loci is a newly described genetic factor strongly associated with the progression of joint damage in RA. Our findings suggest that there are haplotypes in a MMP cluster region that modify the joint destruction in RA in a phasic manner.
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PMID:Association of a specific haplotype across the genes MMP1 and MMP3 with radiographic joint destruction in rheumatoid arthritis. 1514 65

Matrix metalloproteinase (MMP) 10 (stromelysin-2) is known to degrade various components of the extracellular matrix; however, the signals that regulate its expression and its role in lymphoma growth remain unknown. In the present work, we report the up-regulated expression of MMP10 in T lymphoma cells following contact with endothelial cells. The induction of MMP10 was found to be dependent on the specific interaction between LFA-1 and ICAM-1, which play a central role in regulating the expression of genes involved in the rate-limiting steps of lymphoma development. MMP10, but not MMP3 (stromelysin-1), was also up-regulated in human B lymphoma cells following exposure to IL-4, IL-6, and IL-13, but not to IL-1. To gain further insight into the role of MMP10 in lymphoma development, we generated lymphoma cell lines constitutively expressing high levels of MMP10 and studied these cells for their ability to form thymic lymphoma in vivo. Mice injected with lymphoma cells constitutively expressing MMP10 developed thymic lymphoma more rapidly than those injected with control lymphoma cells. These results provide the first in vivo evidence that overexpression of MMP10 promotes tumor development, and indicate that MMP10 induction is an important pathway activated not only upon ICAM-1/LFA-1-mediated intercellular contact, but also following activation of tumor cells with inflammatory cytokines.
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PMID:Stromelysin-2 (matrix metalloproteinase 10) is inducible in lymphoma cells and accelerates the growth of lymphoid tumors in vivo. 1535 4

In a previous study, we observed that some synthetic curcumin analogs inhibited complex formations between Fos-Jun heterodimer and activator protein-1 (AP-1) DNA. These curcumin analogs have been observed to repress the AP-1 transcription in AP-1-transfected cells and they also inhibited the increased expression of Jun/AP-1 protein by 12-O-tetradecanoylphorbol-13-acetate (TPA) in the same cells. After the AP-1 inhibition by curcumin analogs in TPA-treated HT-1080 human fibrosarcoma cells, a decrease in mRNA expression of c-jun and MMP3 (stromelysin-1) has been observed. We also observed that curcumin analogs down-regulated the expression of MMP-9 (gelatinase-B), correlating with cellular invasion and migration in conditions such as tumor invasion and metastasis, through the electrophoretic mobility shift assay and gelatin zymography methods. Curcumin analogs showed an inhibitory effect on angiogenesis by various test methods including chicken chorioallantoic membrane assay, wound migration assay, invasion assay, and tube formation assay. Through the reverse transcriptase-polymerase chain reaction experiment, we confirmed that curcumin analogs down-regulated the expression of angiogenesis-associated genes, VEGF and MMP-9.
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PMID:Synthetic curcumin analogs inhibit activator protein-1 transcription and tumor-induced angiogenesis. 1535 81

Infection of mice with the intestinal bacterial pathogen Citrobacter rodentium results in colonic mucosal hyperplasia and a local Th1 inflammatory response similar to that seen in mouse models of inflammatory bowel disease. Matrix metalloproteinases (MMPs) have been shown to mediate matrix remodeling and cell migration during tissue injury and repair in the intestine. We have previously shown enhanced pathology in infected TNFRp55-/-, IL-12p40-/-, and IFN-gamma-/- mice, and here we show that this is associated with an increase in stromelysin-1 (MMP3) transcripts in colonic tissues. We have therefore investigated the role of MMP3 in colonic mucosal hyperplasia and the local Th1 responses using MMP3-/- mice. In MMP3-/- mice, similar mucosal thickening was observed after infection as in wild-type (WT) mice. Colonic tissues from MMP3-/- mice showed a compensatory increase in the expression of other MMP transcripts, such as MMP7 and MMP12. However, MMP3-/- mice showed delayed clearance of bacteria and delayed appearance of CD4+ T lymphocytes into intestinal lamina propria. CSFE-labeled mesenteric lymph node CD4+ T lymphocytes from infected WT mice migrated in fewer numbers into the mesenteric lymph nodes and colon of MMP3-/- mice than into those of WT mice. These studies show that mucosal remodeling can occur in the absence of MMP3, but that MMP3 plays a role in the migration of CD4+ T lymphocytes to the intestinal mucosa.
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PMID:Impaired immunity to intestinal bacterial infection in stromelysin-1 (matrix metalloproteinase-3)-deficient mice. 1547 62

Newts regenerate lost limbs through a complex process involving dedifferentiation, migration, proliferation, and redifferentiation of cells proximal to the amputation plane. To identify the genes controlling these cellular events, we performed a differential display analysis between regenerating and nonregenerating limbs from the newt Notophthalmus viridescens. This analysis, coupled with a direct cloning approach, identified a previously unknown Notophthalmus collagenase gene (nCol) and three known matrix metalloproteinase (MMP) genes, MMP3/10a, MMP3/10b, and MMP9, all of which are upregulated within hours of limb amputation. MMP3/10b exhibits the highest and most ubiquitous expression and appears to account for the majority of the proteolytic activity in the limb as measured by gel zymography. By testing purified recombinant MMP proteins against potential substrates, we show that nCol is a true collagenase, MMP9 is a gelatinase, MMP3/10a is a stromelysin, and MMP3/10b has an unusually broad substrate profile, acting both as a stromelysin and noncanonical collagenase. Exposure of regenerating limbs to the synthetic MMP inhibitor GM6001 produces either dwarfed, malformed limb regenerates or limb stumps with distal scars. These data suggest that MMPs are required for normal newt limb regeneration and that MMPs function, in part, to prevent scar formation during the regenerative process.
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PMID:Normal newt limb regeneration requires matrix metalloproteinase function. 1570 60

IL-22 is an IFN-IL-10 cytokine family member, which is produced by activated Th1 and NK cells and acts primarily on epithelial cells. Here we demonstrate that IL-22, in contrast to its relative IFN-gamma, regulates the expression of only a few genes in keratinocytes. This is due to varied signal transduction. Gene expressions regulated by IL-22 should enhance antimicrobial defense [psoriasin (S100A7), calgranulin A (S100A8), calgranulin B (S100A9)], inhibit cellular differentiation (e.g., profilaggrin, keratins 1 and 10, kallikrein 7), and increase cellular mobility [e.g., matrix metalloproteinease 1 (MMP1, collagenase 1), MMP3 (stromelysin 1), desmocollin 1]. In contrast, IFN-gamma favored the expression of MHC pathway molecules, adhesion molecules, cytokines, chemokines, and their receptors. The IL-22 effects were transcriptional and either independent of protein synthesis and secretion, or mediated by a secreted protein. Inflammatory conditions, but not keratinocyte differentiation, amplified the IL-22 effects. IL-22 application in mice enhanced cutaneous S100A9 and MMP1 expression. High IL-22 levels in psoriatic skin were associated with strongly up-regulated cutaneous S100A7, S100A8, S100A9, and MMP1 expression. Psoriatic patients showed strongly elevated IL-22 plasma levels, which correlated with the disease severity. Expression of IL-22 and IL-22-regulated genes was reduced by anti-psoriatic therapy. In summary, despite similarities, IFN-gamma primarily amplifies inflammation, while IL-22 may be important in the innate immunity and reorganization of epithelia.
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PMID:IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. 1661 90

Evidence by post-mortem and animal studies suggests that matrix metalloproteinases (MMPs) may play an important role in the pathophysiology of Alzheimer's disease (AD) through degradation of amyloid beta. We investigated in 5999 elderly whether MMP3-haplotypes are associated with cognitive performance over time, dementia and AD. We also explored the association of MMP-3 haplotypes with changes in hippocampal volume and severity of periventricular and subcortical white matter lesions (WML). There was no association between any individual polymorphism or MMP-3 haplotypes and performance in MMSE over time, dementia or AD, and there was no association between MMP-3 genotypes or haplotypes with hippocampal volume or severity of periventricular or subcortical WML. These associations did not differ between strata of APOEepsilon4 genotype. Our observations do not suggest that variation in the MMP3 gene is causally involved in dementia or AD.
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PMID:Matrix metalloproteinase 3 haplotypes and dementia and Alzheimer's disease. The Rotterdam Study. 1731 7


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