-
Cell May 2006One goal of biomedical research is to reliably construct surrogate tissues for replacement therapy and to promote tissue regeneration. In this issue of Cell, Chun et al.... (Review)
Review
One goal of biomedical research is to reliably construct surrogate tissues for replacement therapy and to promote tissue regeneration. In this issue of Cell, Chun et al. (2006) provide insight into the molecular basis of tissue-specific differentiation. The authors show that remodeling of the extracellular matrix by the matrix metalloproteinase MT1-MMP contributes to the three-dimensional development of white adipose tissue in mice.
Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Cell Differentiation; Extracellular Matrix; Matrix Metalloproteinase 14; Matrix Metalloproteinases; Matrix Metalloproteinases, Membrane-Associated; Mice; Mice, Knockout; Tissue Engineering
PubMed: 16678088
DOI: 10.1016/j.cell.2006.04.019 -
Acta Orthopaedica Dec 2009Matrix metalloproteinases (MMPs) and related enzymes (ADAMs, ADAMTS) and their inhibitors control matrix turnover and function. Recent advances in our understanding of... (Review)
Review
Matrix metalloproteinases (MMPs) and related enzymes (ADAMs, ADAMTS) and their inhibitors control matrix turnover and function. Recent advances in our understanding of musculoskeletal conditions such as tendinopathy, arthritis, Dupuytren's disease, degenerative disc disease, and bone and soft tissue healing suggest that MMPs have prominant roles. Importantly, MMPs are amenable to inhibition by cheap, safe, and widely available drugs such as the tetracycline antibiotics and the bisphosphonates. This indicates that these MMP inhibitors, if proven effective for any novel indication, may be quickly brought into clinical practice.
Topics: ADAM Proteins; ADAMTS1 Protein; Bone Matrix; Diphosphonates; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Musculoskeletal Diseases; Prognosis; Tetracyclines; Treatment Outcome
PubMed: 19968600
DOI: 10.3109/17453670903448257 -
Basic & Clinical Pharmacology &... Oct 2014This MiniReview describes the essential biochemical and molecular aspects of matrix metalloproteinases (MMPs) and briefly discusses how they engage in different... (Review)
Review
This MiniReview describes the essential biochemical and molecular aspects of matrix metalloproteinases (MMPs) and briefly discusses how they engage in different diseases, with particular emphasis on cardiovascular diseases. There is compelling scientific evidence that many MMPs, especially MMP-2, play important roles in the development of cardiovascular diseases; inhibition of these enzymes is beneficial to many cardiovascular conditions, sometimes precluding or postponing end-organ damage and fatal outcomes. Conducting comprehensive discussions and further studies on how MMPs participate in cardiovascular diseases is important, because inhibition of these enzymes may be an alternative or an adjuvant for current cardiovascular disease therapy.
Topics: Animals; Cardiovascular Diseases; Disease Models, Animal; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases
PubMed: 24974977
DOI: 10.1111/bcpt.12282 -
International Journal of Molecular... May 2020Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases responsible for tissue remodeling and degradation of extracellular matrix (ECM) proteins.... (Review)
Review
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases responsible for tissue remodeling and degradation of extracellular matrix (ECM) proteins. MMPs may modulate various cellular and signaling pathways in atherosclerosis responsible for progression and rupture of atherosclerotic plaques. The effect of MMPs polymorphisms and the expression of MMPs in both the atherosclerotic plaque and plasma was shown. They are independent predictors of atherosclerotic plaque instability in stable coronary heart disease (CHD) patients. Increased levels of MMPs in patients with advanced cardiovascular disease (CAD) and acute coronary syndrome (ACS) was associated with future risk of cardiovascular events. These data confirm that MMPs may be biomarkers in plaque instability as they target in potential drug therapies for atherosclerosis. They provide important prognostic information, independent of traditional risk factors, and may turn out to be useful in improving risk stratification.
Topics: Acute Coronary Syndrome; Animals; Atherosclerosis; Biomarkers; Cell Movement; Coronary Disease; Disease Progression; Doxycycline; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Lipids; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Plaque, Atherosclerotic; Prognosis; Risk Factors; Signal Transduction; Tissue Distribution
PubMed: 32486345
DOI: 10.3390/ijms21113946 -
Progress in Molecular Biology and... 2017The veins of the lower extremity are equipped with efficient wall, contractile vascular smooth muscle (VSM), and competent valves in order to withstand the high venous... (Review)
Review
The veins of the lower extremity are equipped with efficient wall, contractile vascular smooth muscle (VSM), and competent valves in order to withstand the high venous hydrostatic pressure in the lower limb and allow unidirectional movement of deoxygenated blood toward the heart. The vein wall structure and function are in part regulated by matrix metalloproteinases (MMPs). MMPs are zinc-dependent endopeptidases that are secreted as inactive pro-MMPs by different cells in the venous wall including fibroblasts, VSM, and leukocytes. Pro-MMPs are activated by other MMPs, proteinases, and other endogenous and exogenous activators. MMPs degrade various extracellular matrix (ECM) proteins including collagen and elastin, and could affect other cellular processes including endothelium-mediated dilation, VSM cell migration, and proliferation as well as modulation of Ca signaling and contraction in VSM. It is thought that increased lower limb venous hydrostatic pressure increases hypoxia-inducible factors and other MMP inducers such as extracellular matrix metalloproteinase inducer, leading to increased MMP expression/activity, ECM protein degradation, vein wall relaxation, and venous dilation. Vein wall inflammation and leukocyte infiltration cause additional increases in MMPs, and further vein wall dilation and valve degradation, that could lead to chronic venous disease and varicose veins (VVs). VVs are often presented as vein wall dilation and tortuosity, incompetent venous valves, and venous reflux. Different regions of VVs show different MMP levels and ECM proteins with atrophic regions showing high MMP levels/activity and little ECM compared to hypertrophic regions with little or inactive MMPs and abundant ECM. Treatment of VVs includes compression stockings, venotonics, sclerotherapy, or surgical removal. However, these approaches do not treat the cause of VVs, and other lines of treatment may be needed. Modulation of endogenous tissue inhibitors of metalloproteinases (TIMPs), and exogenous synthetic MMP inhibitors may provide new approaches in the management of VVs.
Topics: Animals; Chronic Disease; Humans; Lower Extremity; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Varicose Veins; Vascular Remodeling
PubMed: 28413031
DOI: 10.1016/bs.pmbts.2017.02.003 -
Pulmonary Medicine 2022Tissue inhibitors of matrix metalloproteinases (TIMP) are a family of four endogenous proteins that primarily function to inhibit the activities of proteases such as the... (Review)
Review
Tissue inhibitors of matrix metalloproteinases (TIMP) are a family of four endogenous proteins that primarily function to inhibit the activities of proteases such as the matrix metalloproteinases (MMP). Altered MMP/TIMP ratios are frequently observed in several human diseases. During aging and disease progression, the extracellular matrix (ECM) undergoes structural changes in which elastin and collagens serve an essential role. MMPs and TIMPs significantly influence the ECM. Classically, elevated levels of TIMPs are suggested to result in ECM accumulation leading to fibrosis, whereas loss of TIMP responses leads to enhanced matrix proteolysis. Here, we outline the known roles of the most abundant TIMP, TIMP2, in pulmonary diseases but also discuss future perspectives in TIMP2 research that could impact the lungs. TIMP2 directly inhibits MMPs, in particular MMP2, but TIMP2 is also required for the activation of MMP2 through its interaction with MMP14. The protease and antiprotease imbalance of MMPs and TIMPs are extensively studied in diseases but recent discoveries suggest that TIMPs, specifically, TIMP2 could play other roles in aging and inflammation processes.
Topics: Humans; Tissue Inhibitor of Metalloproteinase-2; Matrix Metalloproteinase 2; Tissue Inhibitor of Metalloproteinases; Matrix Metalloproteinases; Lung; Biology
PubMed: 36624735
DOI: 10.1155/2022/3632764 -
Molecular Cancer Therapeutics Jun 2018The matrix metalloproteinases (MMP) are a family of proteolytic enzymes that degrade multiple components of the extracellular matrix. A large body of experimental and... (Review)
Review
The matrix metalloproteinases (MMP) are a family of proteolytic enzymes that degrade multiple components of the extracellular matrix. A large body of experimental and clinical evidence has implicated MMPs in tumor invasion, neoangiogenesis, and metastasis, and therefore they represent ideal pharmacologic targets for cancer therapy. From the 1990s to early 2000s, synthetic inhibitors of MMPs (MMPI) were studied in various cancer types. Unexpectedly, despite strongly promising preclinical data, all trials were unsuccessful in reducing tumor burden or improving overall survival; in addition, MMPIs had unforeseen, severe side effects. Two main reasons can explain the failure of MMPIs in clinical trials. It has now become apparent that some MMPs have antitumor effects; therefore, the broad-spectrum MMPIs used in the initial trials might block these MMPs and result in tumor progression. In addition, although MMPs are involved in the early stages of tumor progression, MMPIs were tested in patients with advanced disease, beyond the stage when these compounds could be effective. As more specific MMPIs are now available, MMP targeting could be reconsidered for cancer therapy; however, new trials should be designed to test their antimetastatic properties in early-stage tumors, and endpoints should focus on parameters other than decreasing metastatic tumor burden. .
Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Disease Progression; Disease Susceptibility; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Targeted Therapy; Neoplasms; Treatment Outcome
PubMed: 29735645
DOI: 10.1158/1535-7163.MCT-17-0646 -
International Journal of Molecular... Apr 2017Matrix metalloproteinases (MMPs) are implicated in the degradation of extracellular matrix (ECM). Rheumatoid arthritis (RA) synovial fibroblasts (SFs) produce... (Review)
Review
Matrix metalloproteinases (MMPs) are implicated in the degradation of extracellular matrix (ECM). Rheumatoid arthritis (RA) synovial fibroblasts (SFs) produce matrix-degrading enzymes, including MMPs, which facilitate cartilage destruction in the affected joints in RA. Epigenetic mechanisms contribute to change in the chromatin state, resulting in an alteration of gene transcription. Recently, MMP gene activation has been shown to be caused in RASFs by the dysregulation of epigenetic changes, such as histone modifications, DNA methylation, and microRNA (miRNA) signaling. In this paper, we review the role of MMPs in the pathogenesis of RA as well as the disordered epigenetic mechanisms regulating MMP gene activation in RASFs.
Topics: Arthritis, Rheumatoid; Chromatin; DNA Methylation; Epigenesis, Genetic; Histones; Humans; Matrix Metalloproteinases; MicroRNAs
PubMed: 28441353
DOI: 10.3390/ijms18050905 -
ACS Nano Feb 2019Overexpression and activation of matrix metalloproteinase-9 (MMP-9) is associated with multiple diseases and can serve as a stimulus to activate nanomaterials for...
Overexpression and activation of matrix metalloproteinase-9 (MMP-9) is associated with multiple diseases and can serve as a stimulus to activate nanomaterials for sensing and controlled release. In order to achieve autonomous therapeutics with improved space-time targeting capabilities, several features need to be considered beyond the introduction of an enzyme-cleavable linker into a nanostructure. We introduce guiding principles for a customizable platform using supramolecular peptide nanostructures with three modular components to achieve tunable kinetics and morphology changes upon MMP-9 exposure. This approach enables (1) fine-tuning of kinetics through introduction of ordered/disordered structures, (2) a 12-fold variation in hydrolysis rates achieved by electrostatic (mis)matching of particle and enzyme charge, and (3) selection of enzymatic reaction products that are either cell-killing nanofibers or disintegrate. These guiding principles, which can be rationalized and involve exchange of just a few amino acids, enable systematic customization of enzyme-responsive peptide nanostructures for general use in performance optimization of enzyme-responsive materials.
Topics: Kinetics; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Nanostructures; Peptides
PubMed: 30689363
DOI: 10.1021/acsnano.8b07401 -
Molecules (Basel, Switzerland) Jul 2023Matrix metalloproteinases (MMPs) are identifiable members of proteolytic enzymes that can degrade a wide range of proteins in the extracellular matrix (ECM). MMPs can be... (Review)
Review
Matrix metalloproteinases (MMPs) are identifiable members of proteolytic enzymes that can degrade a wide range of proteins in the extracellular matrix (ECM). MMPs can be categorized into six groups based on their substrate specificity and structural differences: collagenases, gelatinases, stromelysins, matrilysins, metalloelastase, and membrane-type MMPs. MMPs have been linked to a wide variety of biological processes, such as cell transformation and carcinogenesis. Over time, MMPs have been evaluated for their role in cancer progression, migration, and metastasis. Accordingly, various MMPs have become attractive therapeutic targets for anticancer drug development. The first generations of broad-spectrum MMP inhibitors displayed effective inhibitory activities but failed in clinical trials due to poor selectivity. Thanks to the evolution of X-ray crystallography, NMR analysis, and homology modeling studies, it has been possible to characterize the active sites of various MMPs and, consequently, to develop more selective, second-generation MMP inhibitors. In this review, we summarize the computational and synthesis approaches used in the development of MMP inhibitors and their evaluation as potential anticancer agents.
Topics: Humans; Matrix Metalloproteinase Inhibitors; Neoplasms; Matrix Metalloproteinases; Antineoplastic Agents; Extracellular Matrix
PubMed: 37513440
DOI: 10.3390/molecules28145567