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Biochimica Et Biophysica Acta Jan 2010
Topics: Animals; Clinical Trials as Topic; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasms; Protease Inhibitors; Substrate Specificity
PubMed: 20159302
DOI: 10.1016/j.bbamcr.2010.01.016 -
International Journal of Molecular... Aug 2022Matrix metalloproteinases (MMPs) are critical enzymes involved in a variety of cellular processes. MMPs are well known for their ability to degrade the extracellular... (Review)
Review
Matrix metalloproteinases (MMPs) are critical enzymes involved in a variety of cellular processes. MMPs are well known for their ability to degrade the extracellular matrix (ECM) and their extracellular role in cell migration. Recently, more research has been conducted on investigating novel subcellular localizations of MMPs and their intracellular roles at their respective locations. In this review article, we focus on the subcellular localization and novel intracellular roles of two closely related MMPs: membrane-type-1 matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase-2 (MMP-2). Although MT1-MMP is commonly known to localize on the cell surface, the protease also localizes to the cytoplasm, caveolae, Golgi, cytoskeleton, centrosome, and nucleus. At these subcellular locations, MT1-MMP functions in cell migration, macrophage metabolism, invadopodia development, spindle formation and gene expression, respectively. Similar to MT1-MMP, MMP-2 localizes to the caveolae, mitochondria, cytoskeleton, nucleus and nucleolus and functions in calcium regulation, contractile dysfunction, gene expression and ribosomal RNA transcription. Our particular interest lies in the roles MMP-2 and MT1-MMP serve within the nucleus, as they may provide critical insights into cancer epigenetics and tumor migration and invasion. We suggest that targeting nuclear MT1-MMP or MMP-2 to reduce or halt cell proliferation and migration may lead to the development of new therapies for cancer and other diseases.
Topics: Extracellular Matrix; Humans; Matrix Metalloproteinase 14; Matrix Metalloproteinase 2; Matrix Metalloproteinases; Metalloendopeptidases; Neoplasms
PubMed: 36076910
DOI: 10.3390/ijms23179513 -
Molecular Aspects of Medicine Oct 2008Matrix metalloproteinases (MMPs) are now acknowledged as key players in the regulation of both cell-cell and cell-extracellular matrix interactions. They are involved in... (Review)
Review
Matrix metalloproteinases (MMPs) are now acknowledged as key players in the regulation of both cell-cell and cell-extracellular matrix interactions. They are involved in modifying matrix structure, growth factor availability and the function of cell surface signalling systems, with consequent effects on cellular differentiation, proliferation and apoptosis. They play central roles in morphogenesis, wound healing, tissue repair and remodelling in response to injury and in the progression of diseases such as arthritis, cancer and cardiovascular disease. Because of their wide spectrum of activities and expression sites, the elucidation of their potential as drug targets in disease or as important features of the repair process will be dependent upon careful analysis of their role in different cellular locations and at different disease stages. Novel approaches to the specific regulation of individual MMPs in different contexts are also being developed.
Topics: Animals; Arthritis; Extracellular Matrix; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Models, Molecular; Neoplasms; Protein Conformation; Substrate Specificity; Tissue Inhibitor of Metalloproteinases; Vascular Diseases
PubMed: 18619669
DOI: 10.1016/j.mam.2008.05.002 -
Cells Aug 2019The pursuit of matrix metalloproteinase (MMP) inhibitors began in earnest over three decades ago. Initial clinical trials were disappointing, resulting in a negative... (Review)
Review
The pursuit of matrix metalloproteinase (MMP) inhibitors began in earnest over three decades ago. Initial clinical trials were disappointing, resulting in a negative view of MMPs as therapeutic targets. As a better understanding of MMP biology and inhibitor pharmacokinetic properties emerged, it became clear that initial MMP inhibitor clinical trials were held prematurely. Further complicating matters were problematic conclusions drawn from animal model studies. The most recent generation of MMP inhibitors have desirable selectivities and improved pharmacokinetics, resulting in improved toxicity profiles. Application of selective MMP inhibitors led to the conclusion that MMP-2, MMP-9, MMP-13, and MT1-MMP are not involved in musculoskeletal syndrome, a common side effect observed with broad spectrum MMP inhibitors. Specific activities within a single MMP can now be inhibited. Better definition of the roles of MMPs in immunological responses and inflammation will help inform clinic trials, and multiple studies indicate that modulating MMP activity can improve immunotherapy. There is a U.S. Food and Drug Administration (FDA)-approved MMP inhibitor for periodontal disease, and several MMP inhibitors are in clinic trials, targeting a variety of maladies including gastric cancer, diabetic foot ulcers, and multiple sclerosis. It is clearly time to move on from the dogma of viewing MMP inhibition as intractable.
Topics: Animals; Humans; Inflammation; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Structure; United States; United States Food and Drug Administration
PubMed: 31461880
DOI: 10.3390/cells8090984 -
Biology of Reproduction Jul 2016Pregnancy, spontaneous term labor (TL), and postpartum (PP) involution are associated with changes in the cellular and extracellular matrix composition of the uterus....
Pregnancy, spontaneous term labor (TL), and postpartum (PP) involution are associated with changes in the cellular and extracellular matrix composition of the uterus. Both the uterine smooth muscle (myometrium) and the infiltrating peripheral blood leukocytes involved in the activation of labor secrete extracellular matrix-degrading enzymes (matrix metalloproteinases, MMPs) that can modulate cellular behavior and barrier function. MMP expression is induced by mechanical stretch in several tissues. We hypothesized that the expression and activity of myometrial MMPs and their tissue inhibitors (TIMPs) are modulated in preparation for TL and PP involution and are regulated by mechanical stretch of uterine walls imposed by the growing fetus. Myometrial tissues were collected from bilaterally and unilaterally pregnant rats across gestation, TL, and PP. Total RNA and proteins were subjected to real-time PCR and immunoblotting, respectively, and tissue localization and activity was examined by immunohistochemistry and in situ zymography. We found that Mmp7, Mmp11, and Mmp12 mRNA levels were upregulated during TL and PP, while Mmp2, Mmp3, Mmp8, Mmp9, Mmp10, and Mmp13 mRNAs were only upregulated during PP. Timp1-Timp4 were stably expressed throughout gestation with some fluctuations PP. Active MMP2 was induced in the empty uterine horn during gestation and in the gravid PP uterus, suggesting negative regulation by biological mechanical stretch. We conclude that specific subsets of uterine MMPs are differentially regulated in the rat myometrium in preparation for two major events: TL and PP uterine involution.
Topics: Animals; Female; Gene Expression; Matrix Metalloproteinases; Muscle, Smooth; Myometrium; Parturition; Postpartum Period; Pregnancy; Rats; Rats, Wistar
PubMed: 27251092
DOI: 10.1095/biolreprod.115.138248 -
The Biochemical Journal Jun 2016Matrix metalloproteases (MMPs) are crucial components of a complex and dynamic network of proteases. With a wide range of potential substrates, their production and... (Review)
Review
Matrix metalloproteases (MMPs) are crucial components of a complex and dynamic network of proteases. With a wide range of potential substrates, their production and activity are tightly controlled by a combination of signalling events, zymogen activation, post-translational modifications and extracellular inhibition. Slight imbalances may result in the initiation or progression of specific disease states, such as cancer and pathological inflammation. As glycosylation modifies the structures and functions of glycoproteins and many MMPs contain N- or O-linked oligosaccharides, we examine, compare and evaluate the evidence for whether glycosylation affects MMP catalytic activity and other functions. It is interesting that the catalytic sites of MMPs do not contain O-linked glycans, but instead possess a conserved N-linked glycosylation site. Both N- and O-linked oligosaccharides, attached to specific protein domains, endow these domains with novel functions such as the binding to lectins, cell-surface receptors and tissue inhibitors of metalloproteases (TIMPs). Validated glycobiological data on N- and O-linked oligosaccharides of gelatinase B/MMP-9 and on O-linked structures of membrane-type 1 MMP/MMP-14 indicate that in-depth research of other MMPs may yield important insights, e.g. about subcellular localizations and functions within macromolecular complexes.
Topics: Animals; Glycosylation; Humans; Lectins; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Models, Molecular; Protein Binding
PubMed: 27234584
DOI: 10.1042/BJ20151154 -
International Journal of Molecular... Aug 2022This review article aims to describe some of the roles of Matrix metalloproteinases (MMPs) in enamel, dentine, dental caries, hybrid layer degradation, pulp and... (Review)
Review
OBJECTIVES
This review article aims to describe some of the roles of Matrix metalloproteinases (MMPs) in enamel, dentine, dental caries, hybrid layer degradation, pulp and periodontal tissues, throwing light on their current inhibitors. The article addresses the potential of MMPs to serve as biomarkers with diagnostic and therapeutic value.
DESIGN
The sections of this review discuss MMPs' involvement in developmental, remodeling, degradational and turnover aspects of dental and periodontal tissues as well as their signals in the pathogenesis, progress of different lesions and wound healing of these tissues. The literature was searched for original research articles, review articles and theses. The literature search was conducted in PubMed and MEDLINE for articles published in the last 20 years.
RESULTS
119 published papers, two textbooks and two doctoral theses were selected for preparing the current review.
CONCLUSIONS
MMPs are significant proteases, of evident contribution in dental and periapical tissue development, health and disease processes, with promising potential for use as diagnostic and prognostic disease biomarkers. Continuing understanding of their role in pathogenesis and progress of different dental, periapical and periodontal lesions, as well as in dentine-pulp wound healing could be a keystone to future diagnostic and therapeutic regimens.
Topics: Biomarkers; Dental Caries; Humans; Matrix Metalloproteinases; Periodontium
PubMed: 36012195
DOI: 10.3390/ijms23168929 -
Asian Pacific Journal of Cancer... 2014Matrix metalloproteinases (MMPs) are a family of zinc dependent extracellular matrix (ECM) remodelling endopeptidases having the ability to degrade almost all components... (Review)
Review
Matrix metalloproteinases (MMPs) are a family of zinc dependent extracellular matrix (ECM) remodelling endopeptidases having the ability to degrade almost all components of extracellular matrix and implicated in various physiological as well as pathological processes. Carcinogenesis is a multistage process in which alteration of the microenvironment is required for conversion of normal tissue to a tumour. Extracellular matrix remodelling proteinases such as MMPs are principal mediators of alterations observed in the microenvironment during carcinogenesis and according to recent concepts not only have roles in invasion or late stages of cancer but also in regulating initial steps of carcinogenesis in a favourable or unfavourable manner. Establishment of relationships between MMP overproduction and cancer progression has stimulated the development of inhibitors that block proteolytic activity of these enzymes. In this review we discuss the MMP general structure, classification, regulation roles in relation to hallmarks of cancer and as targets for therapeutic intervention.
Topics: Apoptosis; Carcinogenesis; Extracellular Matrix; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Protein Structure, Tertiary; Transcriptional Activation; Tumor Microenvironment
PubMed: 24606423
DOI: 10.7314/apjcp.2014.15.3.1085 -
Biochimica Et Biophysica Acta Dec 2013Cardiac muscle is unique because it contracts ceaselessly throughout the life and is highly resistant to fatigue. The marvelous nature of the cardiac muscle is... (Review)
Review
Cardiac muscle is unique because it contracts ceaselessly throughout the life and is highly resistant to fatigue. The marvelous nature of the cardiac muscle is attributed to its matrix that maintains structural and functional integrity and provides ambient micro-environment required for mechanical, cellular and molecular activities in the heart. Cardiac matrix dictates the endothelium myocyte (EM) coupling and contractility of cardiomyocytes. The matrix metalloproteinases (MMPs) and their tissue inhibitor of metalloproteinases (TIMPs) regulate matrix degradation that determines cardiac fibrosis and myocardial performance. We have shown that MMP-9 regulates differential expression of micro RNAs (miRNAs), calcium cycling and contractility of cardiomyocytes. The differential expression of miRNAs is associated with angiogenesis, hypertrophy and fibrosis in the heart. MMP-9, which is involved in the degradation of cardiac matrix and induction of fibrosis, is also implicated in inhibition of survival and differentiation of cardiac stem cells (CSC). Cardiac matrix is distinct because it renders mechanical properties and provides a framework essential for differentiation of cardiac progenitor cells (CPC) into specific lineage. Cardiac matrix regulates myocyte contractility by EM coupling and calcium transients and also directs miRNAs required for precise regulation of continuous and synchronized beating of cardiomyocytes that is indispensible for survival. Alteration in the matrix homeostasis due to induction of MMPs, altered expression of specific miRNAs or impaired signaling for contractility of cardiomyocytes leads to catastrophic effects. This review describes the mechanisms by which cardiac matrix regulates myocardial performance and suggests future directions for the development of treatment strategies in cardiovascular diseases.
Topics: Animals; Cardiovascular Diseases; Extracellular Matrix; Humans; Matrix Metalloproteinases; Myocardium; Myocytes, Cardiac; Tissue Inhibitor of Metalloproteinases
PubMed: 24055000
DOI: 10.1016/j.bbadis.2013.09.004 -
Relationship between matrix metalloproteinases and the occurrence and development of ovarian cancer.Brazilian Journal of Medical and... May 2017Ovarian cancer is one of the most malignant genital cancers, with a high mortality rate. Many researchers have suggested that matrix metalloproteinases (MMPs) have... (Review)
Review
Ovarian cancer is one of the most malignant genital cancers, with a high mortality rate. Many researchers have suggested that matrix metalloproteinases (MMPs) have remarkably high expression in ovarian cancer tissues. MMPs are considered to be related to the occurrence, development, invasion and metastasis of ovarian cancer. Moreover, some studies have discovered that the unbalance between MMPs and tissue inhibitor of metalloproteinases (TIMPs) are associated with the malignant phenotype of tumors. This review summarizes the latest research progress of MMPs in ovarian cancer. The investigation of MMP mechanism in ovarian cancer will facilitate the development of effective anti-tumor drugs, and thereby improve the survival rate of patients with ovarian cancer.
Topics: Biomarkers, Tumor; Female; Gene Expression; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Ovarian Neoplasms; Tissue Inhibitor of Metalloproteinases
PubMed: 28538838
DOI: 10.1590/1414-431X20176104