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The Journal of Thoracic and... Jan 2007The altered expression of matrix metalloproteinases and their inhibitors influences the formation of atherosclerotic abdominal aortic aneurysms. Their association with...
OBJECTIVES
The altered expression of matrix metalloproteinases and their inhibitors influences the formation of atherosclerotic abdominal aortic aneurysms. Their association with thoracic aneurysms is less clear. This study describes the expression of metalloproteinases and their inhibitors in atherosclerotic and nonatherosclerotic thoracic aneurysms, and compares these with age-matched controls.
METHODS
Matrix metalloproteinase-2 and 9 activity were measured by antibody capture, and tissue inhibitor-1 and 2 levels were measured by enzyme-linked immunosorbent assay in 24 patients with atherosclerotic aneurysms and in 63 patients with nonatherosclerotic aneurysms. Gene expression was assessed with reverse transcriptase polymerase chain reaction. The results were compared with 17 controls.
RESULTS
Data are in nanograms per milligram of protein. Matrix metalloproteinase-2 activity was greater in controls than in the atherosclerotic and nonatherosclerotic groups (80 +/- 67 vs 49 +/- 50 and 35 +/- 44, P = .002). Matrix metalloproteinase-9 activity was greater in the atherosclerotic group than in the nonatherosclerotic group and controls (11.7 +/- 15.7 vs 2.5 +/- 2.2 and 1.7 +/- 1.9, P = .001). Tissue inhibitor-1 and 2 levels were greater in controls than in either aneurysm group (tissue inhibitor of metalloproteinase-1: 376 +/- 192 vs 234 +/- 233 and 174 +/- 148, P = .003; tissue inhibitor of metalloproteinase-2: 143 +/- 74 vs 14 +/- 13 and 27 +/- 43, P < .001). Atherosclerotic aneurysms expressed more matrix metalloproteinase mRNA than controls.
CONCLUSIONS
The metalloproteinase/tissue inhibitor phenotype of atherosclerotic thoracic aneurysms is similar to that of abdominal aneurysms. The diminished expression of metalloproteinases and tissue inhibitors in nonatherosclerotic thoracic aneurysms relative to aged controls may represent a loss of smooth muscle cells.
Topics: Aged; Aortic Aneurysm, Thoracic; Atherosclerosis; Female; Gene Expression; Humans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Middle Aged; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Tissue Inhibitor of Metalloproteinases
PubMed: 17198804
DOI: 10.1016/j.jtcvs.2006.07.036 -
Journal of Molecular Medicine (Berlin,... 2000The zinc- and calcium-dependent family of proteins called the matrix metalloproteinases are collectively responsible for the degradation of the extracellular matrix.... (Review)
Review
The zinc- and calcium-dependent family of proteins called the matrix metalloproteinases are collectively responsible for the degradation of the extracellular matrix. Members of this family such as the collagenases, stromelysins and the gelatinases are involved in the routine tissue remodelling processes such as wound healing, embryonic growth and angiogenesis. Under normal circumstances the proteolytic activity of these proteins are precisely controlled at the transcriptional level, the production of the proteins in their inactive zymogen forms and also by the co-secretion of endogenous inhibitors. Imbalance between the active enzymes and their natural inhibitors leads to the accelerated destruction of connective tissue associated with the pathology of diseases such as rheumatoid and osteoarthritis. The potential for using specific enzyme inhibitors as therapeutic agents to redress this balance has led to intensive research focused on the design, syntheses and molecular structural analyses of low molecular weight inhibitors of this family of proteins. This review describes the essential structural principles and molecular interactions implicated in the innovation of matrix metalloproteinase inhibitors and discusses the features necessary for the specific inhibition of the collagenases.
Topics: Catalytic Domain; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Protease Inhibitors; Protein Conformation; Zinc
PubMed: 10954198
DOI: 10.1007/s001090000113 -
Eye (London, England) May 2005To compare matrix metalloproteinase (MMP) localisation in anterior keratectomy (AK) and lamellar keratectomy (LK) wounds.
AIM
To compare matrix metalloproteinase (MMP) localisation in anterior keratectomy (AK) and lamellar keratectomy (LK) wounds.
METHODS
Wounds were produced in one eye of 24 rabbits. The AK wounds were made to approximately 120 microm in depth and then allowed to re-epithelialise. The LK wounds were of similar depth, but the anterior stroma and epithelium were replaced after a second deeper keratectomy had been performed. Immunohistochemistry was used to localise the MMP-1, -2, -3, and -9 at intervals from 4 h to 14 days following surgery. The contralateral eyes acted as controls.
RESULTS
After an AK wound MMP-1 was present at the leading edge of migrating epithelium after 18 h, while MMP-2 and -9 were localised behind the advancing epithelial edge. The presence of these enzymes rapidly fell to low levels after epithelial closure. There was only faint MMP-3 localisation between days 3 and 7. After an LK wound, MMP-1, -3, and -9 were not detected in the stromal interface, but MMP-2 was present at all time points.
CONCLUSIONS
This study suggests that after an AK wound, MMP-1 is a key mediator of epithelial migration, while MMP-2 and -9, and to a lesser extent MMP-3, may participate in the remodelling of corneal stroma and the reformation of epithelial basement membrane. In contrast, an LK wound results in a much lower stimulus for MMP activation. The action of MMP-2 in stromal repair is thus partly independent of epithelial injury.
Topics: Animals; Cornea; Corneal Stroma; Corneal Surgery, Laser; Epithelium, Corneal; Keratomileusis, Laser In Situ; Lasers, Excimer; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Photorefractive Keratectomy; Postoperative Period; Rabbits; Wound Healing
PubMed: 15332107
DOI: 10.1038/sj.eye.6701557 -
Anti-inflammatory & Anti-allergy Agents... 2015Matrix metalloproteinases (MMPs) contribute to various physiological and pathophysiological processes. An imbalance in MMP activity causes pathological conditions...
BACKGROUND
Matrix metalloproteinases (MMPs) contribute to various physiological and pathophysiological processes. An imbalance in MMP activity causes pathological conditions including inflammatory diseases, cancer, and cardiovascular diseases. Each MMP member has many 3D structures available; therefore, selecting one structure for virtual screening becomes challenging.
METHODS
In this study, we used the cross-docking approach to rank the available MMP structures for their probable successful performance in virtual screening. To determine structures that would offer best average RMSD (root mean square deviation), we performed cross-docking studies on 123 holo (protein-ligand) structures of seven MMP enzyme groups (MMP-1, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, and MMP-13).
RESULTS
MMP enzymes with more flexible residues had fewer structures with RMSD < 2.0 A. Further, same resolution and binding affinities, difference in ligand size, and chemotype of the co-crystalized ligand were parameters that could greatly affect the corresponding cross-dock results and the calculated average RMSD for the structures. Four of the six best MMP-12 receptors, which were identified using the average RMSD metric, had the highest EF1% (emrichment factor) in the retrospective enrichment study.
CONCLUSION
According to the enrichment results, structures with lower average RMSD have a high probability of being appropriate candidates. These study findings will help in receptor selection for an MMP virtual screening protocol and lead to better enrichment of MMP inhibitors.
Topics: Ligands; Matrix Metalloproteinases; Molecular Docking Simulation; Protein Binding; Protein Conformation
PubMed: 26872606
DOI: 10.2174/1871523014666151020095718 -
Genome Biology 2003The matrix metalloproteinase family in humans comprises 23 enzymes, which are involved in many biological processes and diseases. It was previously thought that these... (Review)
Review
The matrix metalloproteinase family in humans comprises 23 enzymes, which are involved in many biological processes and diseases. It was previously thought that these enzymes acted only to degrade components of the extracellular matrix, but this view has changed with the discovery that non-extracellular-matrix molecules are also substrates.
Topics: Animals; Evolution, Molecular; Humans; Matrix Metalloproteinases
PubMed: 12801404
DOI: 10.1186/gb-2003-4-6-216 -
Nature Reviews. Molecular Cell Biology Mar 2002It is 40 years since the first member of what came to be known as the matrix metalloproteinase (MMP) family was described. Structural, molecular and biochemical... (Review)
Review
It is 40 years since the first member of what came to be known as the matrix metalloproteinase (MMP) family was described. Structural, molecular and biochemical approaches have subsequently contributed to piecing together the puzzle of how MMPs work, and how they contribute to various disease processes.
Topics: Animals; Cloning, Molecular; Gene Expression Regulation, Enzymologic; History, 20th Century; Humans; Matrix Metalloproteinases; Models, Biological; Models, Molecular; Protease Inhibitors
PubMed: 11994741
DOI: 10.1038/nrm763 -
Current Medicinal Chemistry Mar 2001Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes involved in the degradation and remodeling of extracellular matrix proteins. The activities of... (Review)
Review
Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes involved in the degradation and remodeling of extracellular matrix proteins. The activities of these enzymes are well regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Chronic stimulation of MMP activities due to an imbalance in the levels of MMPs and TIMPs has been implicated in the pathogenesis of a variety of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. Thus, MMP inhibitors are expected to be useful for the treatment of these disorders. This article reviews briefly the biochemistry of MMPs and evidence for their pathogenic roles using molecular biology approaches. Biomolecular structures used in the design of MMP inhibitors are thoroughly covered. Major emphasis is on recently published potent, small molecular weight MMP inhibitors and their pharmacological properties. Finally, available clinical results of compounds in development are summarized.
Topics: Amino Acid Sequence; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Sequence Data; Molecular Structure; Protease Inhibitors; Protein Conformation
PubMed: 11172697
DOI: 10.2174/0929867013373417 -
Asia-Pacific Journal of Clinical... Aug 2019Osteosarcoma (OS) is one of the most common malignant bone tumors in children and adolescents, and the eighth leading form of childhood cancer. Matrix metalloproteinases... (Review)
Review
Osteosarcoma (OS) is one of the most common malignant bone tumors in children and adolescents, and the eighth leading form of childhood cancer. Matrix metalloproteinases (MMPs) are proteolytic enzymes implicated in certain cancers including OS. In this review, we discuss the mechanism of actions of MMPs in progression of OS, and the therapeutic use of MMPs inhibitors in the treatment of OS with subsequent clinical studies and future management. The expression of MMPs is upregulated in cancer cells by a variety of cytokines and growth factors, and upregulation of MMPs induces degradation of the extracellular matrix that contributes to cell proliferation by releasing growth factors. MMPs promote the detachment and migration of endothelial cells, cross the basement membrane as well as invade the surrounding lymphatic vessels and causes cancer metastasis. The use of selective MMP inhibitors with limited side effects might be promising therapeutic strategy in the treatment of OS. More clinical trials are necessary to evaluate the role of selective MMPs inhibitors in the prevention and treatment of OS along with their assessment of toxicity.
Topics: Bone Neoplasms; Disease Progression; Humans; Matrix Metalloproteinases; Osteosarcoma
PubMed: 31111666
DOI: 10.1111/ajco.13165 -
Experientia Supplementum (2012) 2012
Topics: Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Protease Inhibitors; Structure-Activity Relationship
PubMed: 22642187
DOI: No ID Found -
Thyroid : Official Journal of the... Dec 2000Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade components of the extracellular matrix (ECM) and basement membrane. They play a critical role in... (Review)
Review
Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade components of the extracellular matrix (ECM) and basement membrane. They play a critical role in many physiological and pathological processes, such as tumor metastasis. The original concept-that MMP activity during metastasis is restricted solely to invasion of the basement membrane and destruction of ECM components-has been modified to encompass multiple aspects of tumor progression: tumor establishment, growth, angiogenesis, intravasation, extravasation, and almost all metastatic steps. Moreover, the role of tissue inhibitors of matrix metalloproteinases (TIMPs), originally believed to exhibit anti-invasion properties solely by virtue of their inhibition of MMPs, has been extended to include their multiple biological effects, such as growth promotion. In thyroid neoplasia as well, MMPs, in particular MMP-2, seem to be associated with metastatic potential. It would seem that similar and divergent patterns regulate MMP and TIMP gene expression in benign and malignant human thyrocytes, in many instances in agreement with the concept of MMPs playing the role of stimulating, and TIMPs inhibiting cell invasion.
Topics: Animals; Homeostasis; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Substrate Specificity; Thyroid Gland; Thyroid Neoplasms; Tissue Inhibitor of Metalloproteinases
PubMed: 11201850
DOI: 10.1089/thy.2000.10.1061