-
International Journal of Molecular... Jun 2020In industrialized countries, cancer is the second leading cause of death after cardiovascular disease. Most cancer patients die because of metastases, which consist of... (Review)
Review
In industrialized countries, cancer is the second leading cause of death after cardiovascular disease. Most cancer patients die because of metastases, which consist of the self-transplantation of malignant cells in anatomical sites other than the one from where the tumor arose. Disseminated cancer cells retain the phenotypic features of the primary tumor, and display very poor differentiation indices and functional regulation. Upon arrival at the target organ, they replace preexisting, normal cells, thereby permanently compromising the patient's health; the metastasis can, in turn, metastasize. The spread of cancer cells implies the degradation of the extracellular matrix by a variety of enzymes, among which the matrix metalloproteinase (MMP)-9 is particularly effective. This article reviews the available published literature concerning the important role that MMP-9 has in the metastatic process. Additionally, information is provided on therapeutic approaches aimed at counteracting, or even preventing, the development of metastasis via the use of MMP-9 antagonists.
Topics: Cell Line, Tumor; Extracellular Matrix; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms
PubMed: 32630531
DOI: 10.3390/ijms21124526 -
Zebrafish 2008The secretome is a functionally rich proteome subset, including cellular membrane and extracellular proteins processed through the secretory pathway. In this study,... (Comparative Study)
Comparative Study
The secretome is a functionally rich proteome subset, including cellular membrane and extracellular proteins processed through the secretory pathway. In this study, Danio rerio and Homo sapiens RefSeq proteins were analyzed with SignalP, TargetP, Phobius, and pTarget algorithms. About 16.5% of the zebrafish proteome and 17.0% of the human proteome possessed predicted N-terminal signal sequences. Nearly half of these proteins were subsequently classified as soluble, as they lacked predicted transmembrane domains. The soluble proteins were further subclassified, predicting 1345 (3.8%) zebrafish and 1207 (3.2%) human proteins as extracellular. Comparison of the zebrafish and human soluble secretome proteins identified 372 as orthologs, on the basis of reciprocal BLAST best hits. The computational characterization of the zebrafish proteins found many more members of the secretome than annotated in the SwissProt database. Only 180 of the 2078 zebrafish SwissProt protein entries, and 995 of the 19,294 human SwissProt protein entries were annotated with secreted protein locales. A specific investigation of the fibroblast growth factor and matrix metalloproteinase (MMP) protein families confirmed the prediction data and generated annotation of three additional putative MMP zebrafish proteins. This study presents the first known published description of the zebrafish secretome since the completion of the zebrafish genome sequencing project.
Topics: Animals; Computational Biology; Fibroblast Growth Factors; Gene Expression Profiling; Humans; Matrix Metalloproteinases; Protein Sorting Signals; Proteome; Software; Zebrafish; Zebrafish Proteins
PubMed: 18554177
DOI: 10.1089/zeb.2008.0529 -
Arthritis and Rheumatism Mar 2001To examine by immunohistochemistry the relative distributions of 6 matrix metalloproteinases (MMPs 1, 2, 3, 8, 9, and 13) and the 2 proinflammatory cytokines...
OBJECTIVE
To examine by immunohistochemistry the relative distributions of 6 matrix metalloproteinases (MMPs 1, 2, 3, 8, 9, and 13) and the 2 proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha) in osteoarthritic (OA) cartilage compared with normal, age-matched articular cartilage.
METHODS
Articular cartilage samples were obtained from the tibial plateau of OA knees removed at arthroplasty and from normal, nonarthritic, knees obtained at autopsy. Specimens were promptly fixed in Carnoy's fixative, processed, embedded in paraffin, sectioned, and examined by immunohistochemistry for MMP and cytokine production. In addition, human articular chondrocytes (HAC) were treated in vitro with either IL-1beta, TNFalpha, or phorbol myristate acetate (PMA) to assess their potential to produce each of the MMPs, as determined by Western blotting and gelatin zymography.
RESULTS
Immunodetection of the collagenases (MMPs 1, 8, and 13) and stromelysin 1 (MMP-3) was demonstrated in a proportion of chondrocytes in the superficial zone of almost all of the OA specimens that had degenerative matrix changes. The gelatinases (MMPs 2 and 9) were also demonstrated by immunohistochemistry but were not so prominent. IL-1beta- and TNFalpha-positive chondrocytes were also observed in a proportion of cells in the superficial zones of OA specimens. Much less immunostaining for MMPs and cytokines was observed in the deep zone of all OA specimens, where the cartilage matrix and chondrocyte morphology appeared normal. In contrast, full-thickness normal cartilage specimens showed virtually no immunostaining for these MMPs or cytokines. Confirmation that chondrocytes can produce these 6 MMPs was obtained from HAC cultures treated with either IL-1beta, TNFalpha, or PMA; conditioned medium from activated HAC contained all the MMPs demonstrated by immunohistochemistry. Dual immunolocalization studies of OA cartilage specimens demonstrated the coexpression of IL-1 with MMP-8 by individual chondrocytes in situ.
CONCLUSION
These results indicate that the superficial zone of OA cartilage specimens, which is characterized by fibrillations, chondrocyte clusters, and degenerative matrix changes, contains a variable proportion of cells that immunostain for IL-1beta, TNFalpha, and 6 different MMPs. These observations support the concept that cytokine-MMP associations reflect a modified chondrocyte phenotype and an intrinsic process of cartilage degradation in OA.
Topics: Aged; Cartilage, Articular; Chondrocytes; Collagenases; Humans; Immunohistochemistry; Interleukin-1; Matrix Metalloproteinase 1; Matrix Metalloproteinase 13; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Matrix Metalloproteinase 8; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Osteoarthritis, Knee; Severity of Illness Index; Tumor Necrosis Factor-alpha
PubMed: 11263773
DOI: 10.1002/1529-0131(200103)44:3<585::AID-ANR107>3.0.CO;2-C -
The Journal of Experimental Medicine Sep 2005During pathologic vessel remodeling, vascular smooth muscle cells (VSMCs) embedded within the collagen-rich matrix of the artery wall mobilize uncharacterized... (Comparative Study)
Comparative Study
During pathologic vessel remodeling, vascular smooth muscle cells (VSMCs) embedded within the collagen-rich matrix of the artery wall mobilize uncharacterized proteolytic systems to infiltrate the subendothelial space and generate neointimal lesions. Although the VSMC-derived serine proteinases, plasminogen activator and plasminogen, the cysteine proteinases, cathepsins L, S, and K, and the matrix metalloproteinases MMP-2 and MMP-9 have each been linked to pathologic matrix-remodeling states in vitro and in vivo, the role that these or other proteinases play in allowing VSMCs to negotiate the three-dimensional (3-D) cross-linked extracellular matrix of the arterial wall remains undefined. Herein, we demonstrate that VSMCs proteolytically remodel and invade collagenous barriers independently of plasmin, cathepsins L, S, or K, MMP-2, or MMP-9. Instead, we identify the membrane-anchored matrix metalloproteinase, MT1-MMP, as the key pericellular collagenolysin that controls the ability of VSMCs to degrade and infiltrate 3-D barriers of interstitial collagen, including the arterial wall. Furthermore, genetic deletion of the proteinase affords mice with a protected status against neointimal hyperplasia and lumen narrowing in vivo. These studies suggest that therapeutic interventions designed to target MT1-MMP could prove beneficial in a range of human vascular disease states associated with the destructive remodeling of the vessel wall extracellular matrix.
Topics: Animals; Apoptosis; Arteries; Cell Movement; Cloning, Molecular; Collagen; Extracellular Matrix; Fluorescent Antibody Technique; Gene Transfer Techniques; In Situ Nick-End Labeling; Male; Matrix Metalloproteinase 14; Matrix Metalloproteinases; Matrix Metalloproteinases, Membrane-Associated; Mice; Mice, Mutant Strains; Microscopy, Electron; Myocytes, Smooth Muscle; Reverse Transcriptase Polymerase Chain Reaction; Vascular Diseases
PubMed: 16147977
DOI: 10.1084/jem.20050607 -
Mediators of Inflammation 2015The aim of this study is to determine the mechanism of sepsis-induced vascular hyperpermeability and the beneficial effect of glucocorticoid in protecting vascular...
The aim of this study is to determine the mechanism of sepsis-induced vascular hyperpermeability and the beneficial effect of glucocorticoid in protecting vascular endothelium. Male Sprague-Dawley rats were given either a bolus intraperitoneal injection of a nonlethal dose of LPS (Escherichia coli 055:B5, 10 mg/kg, Sigma) or vehicle (pyrogen-free water). Animals of treatment groups were also given either dexamethasone (4 mg/kg, 30 min prior to LPS injection) or the matrix metalloproteinases (MMPs) inhibitor doxycycline (4 mg/kg, 30 min after LPS injection). Both activities and protein levels of MMP-2 (p < 0.001) and MMP-9 (p < 0.001) were significantly upregulated in aortic homogenates from LPS-treated rats, associated with decreased ZO-1 (p < 0.001) and syndecan-1 (p = 0.011) protein contents. Both dexamethasone and doxycycline could significantly inhibit MMPs activity and reserve the expressions of ZO-1 and syndecan-1. The inhibition of MMPs by dexamethasone was significantly lower than that by doxycycline, while the rescue of syndecan-1 expression from LPS-induced endotoxemic rat thoracic aorta was significantly higher in the dexamethasone-treated compared to the doxycycline-treated (p = 0.03). In conclusion, activation of MMPs plays important role in regulating ZO-1 and syndecan-1 protein levels in LPS mediated endothelial perturbation. Both dexamethasone and doxycycline inhibit activation of MMPs that may contribute to the rescue of ZO-1 and syndecan-1 expression.
Topics: Animals; Aorta; Dexamethasone; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Female; Glycocalyx; Immunoblotting; Immunohistochemistry; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Rats; Syndecan-1; Zonula Occludens-1 Protein
PubMed: 26199464
DOI: 10.1155/2015/912726 -
Pancreatology : Official Journal of the... Aug 2021Severe acute pancreatitis (SAP) has high morbidity and mortality but there are no widely accepted predictive biomarkers in clinical use. Matrix metalloproteinases (MMPs)...
OBJECTIVES
Severe acute pancreatitis (SAP) has high morbidity and mortality but there are no widely accepted predictive biomarkers in clinical use. Matrix metalloproteinases (MMPs) are active in tissue destruction and inflammatory responses. We studied whether serum levels of activated MMP-8 (aMMP-8), MMP-9 and their regulators tissue inhibitor of matrix metalloproteinases (TIMP)-1, myeloperoxidase (MPO) and human neutrophil elastase (HNE) could predict the development of SAP.
METHODS
The study comprised 214 AP patients (revised Atlanta classification: 142 mild, MAP; 54 moderately severe, MSAP; 18 SAP) referred to Helsinki University Hospital. A venous blood sample was taken within 72 h from the onset of symptoms. Serum levels of aMMP-8 were determined using immunofluorometric assay, and those of MMP-9, TIMP-1, MPO and HNE using enzyme-linked immunosorbent assay. AP groups were compared using Jonckheere-Terpstra test and predictive value for SAP was analyzed using receiver operating characteristics (ROC) analysis.
RESULTS
Serum aMMP-8 levels were higher in SAP (median 657 ng/ml, interquartile range 542-738 ng/ml) compared to MSAP (358 ng/ml, 175-564 ng/ml; p < 0.001) and MAP (231 ng/ml, 128-507 ng/ml; p < 0.001). Similar trend was seen with TIMP-1 and MPO. In ROC analysis aMMP-8, MPO and TIMP-1 emerged as potential markers for the development of SAP (areas under ROC curves 0.83, 0.71 and 0.69, respectively).
CONCLUSIONS
Serum aMMP-8 measured early in the course of AP (within 72 h of symptom onset) predicted the development of SAP.
Topics: Acute Disease; Biomarkers; Humans; Matrix Metalloproteinase 8; Matrix Metalloproteinase 9; Pancreatitis; Tissue Inhibitor of Metalloproteinase-1
PubMed: 33846092
DOI: 10.1016/j.pan.2021.03.022 -
Clinical Chemistry and Laboratory... 2005Matrix metalloproteinases are a family of zinc-dependent proteinases which are involved in the breakdown and remodeling of extracellular matrix. As children grow and... (Comparative Study)
Comparative Study
Matrix metalloproteinases are a family of zinc-dependent proteinases which are involved in the breakdown and remodeling of extracellular matrix. As children grow and adolescents reach pubescence, their bodies undergo changes that require age-related morphogenesis of the extracellular matrix, possibly requiring unique patterns of matrix metalloproteinase (MMP) expression during periods of rapid tissue growth (i.e., childhood) or accelerated tissue remodeling and expansion (i.e., adolescence). Therefore, we have characterized age-specific and gender-specific differences in circulating concentrations of MMPs (specifically MMP-1, -2, -3, -8 and -9) in 189 serum samples obtained from healthy subjects, aged 2-18 years. MMP concentrations were measured using Fluorokine MultiAnalyte Profiling kits and a Luminex Bioanalyzer, as well as by commercial ELISA. Serum levels of MMP-1, -2, -3, -8, and -9 in healthy pediatric subjects represent log-normal distributions. MMP-2 was significantly negatively correlated with age (r=-0.29; p<0.001), while MMP-3 was significantly positively correlated with age (r=0.38; p<0.001). Although plasma, not serum, is considered the appropriate blood sample for measurement of MMP-8 and -9, serum levels of MMP-8 and -9 were also found to be highly positively correlated with each other (r=0.76; p<0.01). MMP results obtained by Fluorokin MultiAnalyte Profiling methods correlated well with conventional ELISA methods and use of this technology provided several advantages over ELISA.
Topics: Adolescent; Adult; Biosensing Techniques; Child; Enzyme-Linked Immunosorbent Assay; Female; Humans; Luminescent Measurements; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Matrix Metalloproteinase 8; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Reference Values; Reproducibility of Results; Sensitivity and Specificity
PubMed: 16309379
DOI: 10.1515/CCLM.2005.238 -
Respiratory Research 2001Despite much information on their catalytic properties and gene regulation, we actually know very little of what matrix metalloproteinases (MMPs) do in tissues. The... (Review)
Review
Despite much information on their catalytic properties and gene regulation, we actually know very little of what matrix metalloproteinases (MMPs) do in tissues. The catalytic activity of these enzymes has been implicated to function in normal lung biology by participating in branching morphogenesis, homeostasis, and repair, among other events. Overexpression of MMPs, however, has also been blamed for much of the tissue destruction associated with lung inflammation and disease. Beyond their role in the turnover and degradation of extracellular matrix proteins, MMPs also process, activate, and deactivate a variety of soluble factors, and seldom is it readily apparent by presence alone if a specific proteinase in an inflammatory setting is contributing to a reparative or disease process. An important goal of MMP research will be to identify the actual substrates upon which specific enzymes act. This information, in turn, will lead to a clearer understanding of how these extracellular proteinases function in lung development, repair, and disease.
Topics: Animals; Humans; Lung; Matrix Metalloproteinase 12; Matrix Metalloproteinase 7; Matrix Metalloproteinases; Metalloendopeptidases; Substrate Specificity
PubMed: 11686860
DOI: 10.1186/rr33 -
Dental and Medical Problems 2023Dental caries is initiated through mineral dissolution by bacterial acids and collagen degradation by endogenous proteolytic enzymes, mainly collagenolytic matrix...
BACKGROUND
Dental caries is initiated through mineral dissolution by bacterial acids and collagen degradation by endogenous proteolytic enzymes, mainly collagenolytic matrix metalloproteinases (MMPs).
OBJECTIVES
The present research aimed to evaluate the relationship between severe early childhood caries (S-ECC) and salivary MMP-8 and MMP-20 concentrations.
MATERIAL AND METHODS
Fifty children aged 36-60 months were assigned to either the caries-free (control) group or the S-ECC group. Standard clinical examinations were performed, and approx. 1 mL of expectorated unstimulated whole saliva was collected from all participants. In the S-ECC group, the sampling was repeated 3 months after restorative treatment. All samples were analyzed for the salivary concentrations of MMP-8 and MMP-20, using the enzyme-linked immunosorbent assay (ELISA). Statistical analysis employed the t test, the Mann-Whitney U test, the χ2 test, Fisher's exact test, and the paired samples t test. The level of significance was set at 0.05.
RESULTS
At baseline, the subjects in the S-ECC group presented with significantly elevated levels of MMP-8 as compared to the control group. However, the salivary concentration of MMP-20 did not exhibit a significant difference between the 2 groups. A significant reduction occurred in the levels of MMP-8 and MMP-20 3 months after restorative treatment in the S-ECC group.
CONCLUSIONS
The salivary levels of MMP-8 and MMP-20 were significantly affected by dental restorative treatment in children. Furthermore, MMP-8 was observed to be a better indicator of the dental caries status than MMP-20.
Topics: Child; Humans; Child, Preschool; Dental Caries; Matrix Metalloproteinase 8; Matrix Metalloproteinase 20; Saliva
PubMed: 37327106
DOI: 10.17219/dmp/142564 -
Anti-inflammatory & Anti-allergy Agents... 2020The critical link between cancer and inflammation has been known for many years. This complex network was further complexed by revealing the association of the matrix... (Review)
Review
The critical link between cancer and inflammation has been known for many years. This complex network was further complexed by revealing the association of the matrix metalloproteinase family members with inflammatory cytokines, which were previously known to be responsible for the development of metastasis. This article summarizes the current studies which evaluate the relationship between cancer and inflammatory microenvironment as well as the roles of MMPs on invasion and metastasis together.
Topics: Cytokines; Humans; Inflammation; Matrix Metalloproteinases; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Tumor Microenvironment
PubMed: 32178620
DOI: 10.2174/1871523018666191023141807