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Balasa, Rodica, Ciurba Bianca, Voidezan Septimiu, Simu Iunius, Hutanu Adina, Andone Sebastian, Romaniuc Andreea, Motataianu Anca i Maier Smaranda. "The Matrix Metalloproteinases Panel in Multiple Sclerosis Patients Treated with Natalizumab: A Possible Answer to Natalizumab Non- Responders". CNS & Neurological Disorders - Drug Targets 17, nr 6 (28.08.2018): 464–72. http://dx.doi.org/10.2174/1871527317666180703102536.
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Background: In the lymphocyte migration across the blood-brain barrier (BBB) in multiple sclerosis (MS), matrix metalloproteinases (MMPs) play an important role in the degradation of the basal membrane. Natalizumab (NAT), a monoclonal antibody, binds to the alpha-4 (α4) integrin leading to BBB impermeability. Approximately 30% of NAT-treated patients show clinical or MRI signs of BBB disruption. Objective: To determine whether NAT significantly influences the MMPs serum levels and to what extent these could be used as biomarkers in relapsing-remitting MS (RRMS) patients. Materials and Methods: This prospective study over a period of 8 months of NAT treatment, included 30 RRMS patients (mean age 38 ± 6 years; mean MS duration 12 ± 5 years), of which ten were initially naive to NAT and 15 were healthy controls. We determined the serum levels of the MMPs Panel (MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP12, and MMP13) quantified by a multiplex method at the beginning and end of the study. Results: After 8 months of NAT treatment, a statistically significant decrease was found in MMP9, MMP2, MMP3, MMP8, and MMP10 levels. Relapses during the study were correlated with a variation of MMP12 and MMP13 serum levels. MMP9 had the most numerous correlations with the EDSS score, Rio score, and duration of NAT treatment. MMPs signature (the sum of all MMPs) and the MMP9/MMP2 ratio significantly decreased during the study. Conclusion: 1. The serum level of MMP9 significantly decreased by NAT treatment and correlates with MS activity; 2. After eight months of NAT treatment, the MMPs signature and the MMP9/MMP2 ratio decreased; 3. MMP9 might be used as a biomarker in MS patients treated with NAT.
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Bartnykaitė, Agnė, Aistė Savukaitytė, Justina Bekampytė, Rasa Ugenskienė, Danguolė Laukaitienė, Erika Korobeinikova, Jurgita Gudaitienė i Elona Juozaitytė. "The Role of Matrix Metalloproteinase Single-Nucleotide Polymorphisms in the Clinicopathological Properties of Breast Cancer". Biomedicines 10, nr 8 (4.08.2022): 1891. http://dx.doi.org/10.3390/biomedicines10081891.
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(1) Background. Breast cancer is the leading cancer type among women. Despite convenient diagnostics at early stages, there is a need for continuous monitoring to predict more aggressive or recurring breast cancer forms. The evidence suggests that the detection of genetic biomarkers could help in improving disease management and reduce mortality. Matrix metalloproteinases (MMPs) are a large family of enzymes that perform physiologically relevant functions and have the potential properties to be biomarkers for cancer assessment. We aimed to evaluate the contribution and association of single-nucleotide polymorphisms (SNPs) in MMP genes (MMP1, MMP2, MMP3, MMP7, MMP8, MMP9) with clinicopathological breast-cancer features. (2) Methods. In this study, 100 breast cancer patients were genotyped by polymerase chain reaction–restriction fragment length polymorphism methodology (PCR–RFLP). (3) Results. The presence of the MMP7 rs11568818 A allele was associated with lower chances for poorly differentiated breast cancer. The lower possibility for HER2-positive breast cancer was associated with the presence of the MMP9 rs3918242 C allele. (4) Conclusions. These results indicate that MMP7 rs11568818 and MMP9 rs3918242 are potential biomarkers for the anticipation of breast cancer aggressiveness.
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Yang, Hui, Carlos E. Bueso-Ramos, Sherry A. Pierce, Yue Wei, Zhihong Fang, Martin Nguyen, Michael Fernadez, Marylou Cardenas-Turanzas, Hagop M. Kantarjian i Guillermo Garcia-Manero. "Expression Profiles of Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Metalloproteinases (TIMPs) in Myelodysplastic Syndromes (MDS): Level of MMP-9 Is Associated with Improved Prognosis in MDS Patients". Blood 120, nr 21 (16.11.2012): 3845. http://dx.doi.org/10.1182/blood.v120.21.3845.3845.
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Abstract Abstract 3845 Introduction: Matrix metalloproteinases (MMPs) belong to a unique family of zinc dependent endopeptidases, they are strictly regulated by their endogenous inhibitors called tissue inhibitor of MMPs (TIMPs). MMPs have been associated with tumorigenesis. In addition to their role in extracellular matrix turnover and cancer cell migration, MMPs regulate signaling pathways that control cell growth, inflammation, or angiogenesis and may even work in nonproteolytic manner. MMPs play a key role during invasion and metastasizing of cancer cells and they have been shown to be associated to invasive phenotype and poor prognosis in several solid tumors. Little is known about their role in MDS. A total of 23 different human MMPs and 4 TIMPs have been identified. To better understand the role of MMPs in MDS, we performed an expression profile screen study by QPCR to detect the expression level of all MMP and TIMP family members, except MMP23, in CD34+ cells from a cohort (N=10) of newly diagnosed, untreated patients with MDS, and compared the expression level with CD34+ cells from 5 normal donors. Of these 26 genes, we identified MMP2, MMP8, MMP9, MMP25, MMP28, TIMP1, TIMP2 and TIMP3 as aberrantly up-regulated genes in MDS and expanded the study to a larger cohort of patients to correlate with clinical features and clinical outcomes. Methods: CD34+ cells from 98 newly diagnosed patients with MDS and 5 normal donors were evaluated for MMP2, MMP8, MMP9, MMP25, MMP28, TIMP1, TIMP2 and TIMP3 expression profiling. CD34+ cells were sorted from patients and normal donor bone marrow. Total cellular RNA was isolated using Trizol, cDNA was obtained by using TaqMan reverse transcription reagent (Applied Biosystems). For real-time PCR, all assays were purchased from Applied Biosystems and analyzed with an Applied Biosystems Prism 7500 Sequencing detection system. GAPDH was used as internal control. Immunohistochemistry was used to detect MMP9 protein level in cytospin from CD34+ cells. MMP9 abtibody was obtained from R&D systems, MMP9 ELISA kit (R&D systems) was used to detect the MMP9 protein level in bone marrow plasma. Results: For the 98 MDS patients studied, 78% were older than 60 years; by IPSS score, 17 (17.3%) low risk, 35 (35.7%) INT-1, 24 (24.5%) INT-2, 10 (10.2%) high risk, 12 (12.2%) not available. By Cytogenetics, diploid 44 (45%), 20q- 7(7%), −5/5q- 7 (7%), −7/7q- 7 (7%), −5/5q- and −7/7q- 6 (6%), 8+ 6 (6%), IM 6 (6%), MISC 14 (14%). By QPCR and comparing MDS CD34+ cells with normal CD34+ cells, aberrant up-regulation (fold>2) of MMP2, MMP8, MMP9, MMP25, MMP28, TIMP1, TIMP2 and TIMP3 was detected in 40%, 93.8%, 94%, 84%, 15.6%, 45%, 21% and 27% of patients respectively. Up-regulation of MMP8, MMP9 and MMP25 were significant with a mean fold value 350.7 (0–3363.7), 1112.4 (0–15641) and 143.8 (0–1017.9) respectively. We performed MMP9 immunohistochemistry of MDS CD34+ cytospins from 16 pts with higher and lower MMP9 RNA relative expression level and found consistent protein expression level in cytoplasm. No elevated MMP9 protein levels were detected in bone marrow plasma. We then performed an analysis of associations with clinical variables and observed that relative expression value of MMP9 was associated with lower bone marrow blast (p=0.001) and longer survival (p=0.02) (figure 1). We did not found association between survival and the other 7 up-regulated genes. Conclusions: Bone marrow CD34+ cells from patients with MDS have abnormal up-regulation of MMP2, MMP8, MMP9, MMP25, MMP28, TIMP1, TIMP2 and TIMP3. MMP9 up-regulation is associated with longer survival. Our results suggest that MMP-9 could be a useful prognostic indicator for MDS and that this family of proteins needs further study in MDS. Disclosures: No relevant conflicts of interest to declare.
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Coven, İlker, Ozge Ozer, Ozlem Ozen, Feride İffet Şahin i Nur Altinors. "Presence of matrix metalloproteinase–2 and tissue inhibitor matrix metalloproteinase–2 gene polymorphisms and immunohistochemical expressions in intracranial meningiomas". Journal of Neurosurgery 121, nr 6 (grudzień 2014): 1478–82. http://dx.doi.org/10.3171/2014.8.jns13515.
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Object Meningiomas are benign extraaxial tumors with a slow progression. Some of them, in spite of being benign in nature, may show an aggressive progression pattern. To investigate the behavioral characteristics of meningiomas, researchers have studied matrix metalloproteinases (MMPs), their tissue inhibitors (TIMPs), interstitial collagens, proteins, vascular endothelial growth factors (VEGF), and tumor necrosis factors. Methods In this study, the authors investigated MMP2 and TIMP2 gene polymorphisms in formalin-fixed paraffin-embedded tissue samples obtained from meningioma patients who had previously undergone surgery at the authors' institution. In addition, brain invasion, Ki-67 index, and MMP-2 and TIMP-2 expressions were investigated using immunohistochemical methods. MMP2 (735C>T, 1575G>A, 1306C>T) and TIMP2 (418G>C, 303C>T) gene polymorphisms were investigated from paraffin-embedded tissue sections using the polymerase chain reaction–restriction fragment length polymorphism method. Results There were statistically significant differences between genotype (p = 0.001) and allele frequencies (p = 0.001 and OR 7.4 [95% CI 1.5–36.2]) in patient and control groups for MMP2 1306C>T polymorphism. The authors did not find a statistically significant difference for other polymorphisms. GA genotype was found to be more frequent when brain invasion was suspected for MMP2 1575G>A polymorphism (p = 0.006). There was not a statistically significant difference for other MMP2 or TIMP2 gene polymorphisms. Conclusions The authors' results support the importance of MMPs and their tissue inhibitors in meningioma pathogenesis. In future studies, these gene polymorphisms, especially MMP2 1306C>T and 1575G>A, should be investigated for meningioma or brain invasion susceptibility in larger study groups.
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WIPFF, JULIEN, PHILIPPE DIEUDE, JEROME AVOUAC, KIET TIEV, ERIC HACHULLA, JEAN-LUC CRACOWSKI, ELIZABETH DIOT i in. "Association of Metalloproteinase Gene Polymorphisms with Systemic Sclerosis in the European Caucasian Population". Journal of Rheumatology 37, nr 3 (28.01.2010): 599–602. http://dx.doi.org/10.3899/jrheum.090973.
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Objective.Systemic sclerosis (SSc) is classified among the complex genetic disorders and is characterized by massive extracellular matrix deposits. These may be due to overactivation of transforming growth factor ß that may be in part a result of abnormal remodeling of extracellular matrix and microfibrils. Metalloproteinases (MMP) are a family of proteolytic enzymes, and MMP 2, 9, and 14 contribute to the degradation of microfibrils. Our aim was to determine whether polymorphisms of the MMP2, MMP9, and MMP14 genes confer susceptibility to SSc in a large population.Methods.A case–control study was performed in 659 SSc patients and 511 healthy matched controls from a European Caucasian population. Six Tag single-nucleotide polymorphisms (SNP) of the MMP2 gene and 2 SNP of MMP9 and MMP14 genes were genotyped.Results.All SNP were in Hardy-Weinberg equilibrium in the control population. There was no association between the MMP2, MMP9, and MMP14 variants we investigated and SSc for allelic and genotype frequencies. No association was observed for the different subphenotypes of SSc patients.Conclusion.Our results in a large cohort of European Caucasian SSc patients do not support that MMP2, MMP9, and MMP14 genes are involved in the genetic background of SSc.
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Detry, Benoit, Charlotte Erpicum, Jenny Paupert, Silvia Blacher, Catherine Maillard, Françoise Bruyère, Hélène Pendeville i in. "Matrix metalloproteinase-2 governs lymphatic vessel formation as an interstitial collagenase". Blood 119, nr 21 (24.05.2012): 5048–56. http://dx.doi.org/10.1182/blood-2011-12-400267.
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Abstract Lymphatic dysfunctions are associated with several human diseases, including lymphedema and metastatic spread of cancer. Although it is well recognized that lymphatic capillaries attach directly to interstitial matrix mainly composed of fibrillar type I collagen, the interactions occurring between lymphatics and their surrounding matrix have been overlooked. In this study, we demonstrate how matrix metalloproteinase (MMP)–2 drives lymphatic morphogenesis through Mmp2-gene ablation in mice, mmp2 knockdown in zebrafish and in 3D-culture systems, and through MMP2 inhibition. In all models used in vivo (3 murine models and thoracic duct development in zebrafish) and in vitro (lymphatic ring and spheroid assays), MMP2 blockage or down-regulation leads to reduced lymphangiogenesis or altered vessel branching. Our data show that lymphatic endothelial cell (LEC) migration through collagen fibers is affected by physical matrix constraints (matrix composition, density, and cross-linking). Transmission electron microscopy and confocal reflection microscopy using DQ-collagen highlight the contribution of MMP2 to mesenchymal-like migration of LECs associated with collagen fiber remodeling. Our findings provide new mechanistic insight into how LECs negotiate an interstitial type I collagen barrier and reveal an unexpected MMP2-driven collagenolytic pathway for lymphatic vessel formation and morphogenesis.
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Ren, Xiaoyu, Graham D. Lamb i Robyn M. Murphy. "Distribution and activation of matrix metalloproteinase-2 in skeletal muscle fibers". American Journal of Physiology-Cell Physiology 317, nr 3 (1.09.2019): C613—C625. http://dx.doi.org/10.1152/ajpcell.00113.2019.
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A substantial intracellular localization of matrix metalloproteinase 2 (MMP2) has been reported in cardiomyocytes, where it plays a role in the degradation of the contractile apparatus following ischemia-reperfusion injury. Whether MMP2 may have a similar function in skeletal muscle is unknown. This study determined that the absolute amount of MMP2 is similar in rat skeletal and cardiac muscle and human muscle (~10–18 nmol/kg muscle wet wt) but is ~50- to 100-fold less than the amount of calpain-1. We compared mechanically skinned muscle fibers, where the extracellular matrix (ECM) is completely removed, with intact fiber segments and found that ~30% of total MMP2 was associated with the ECM, whereas ~70% was inside the muscle fibers. Concordant with whole muscle fractionation, further separation of skinned fiber segments into cytosolic, membranous, and cytoskeletal and nuclear compartments indicated that ~57% of the intracellular MMP2 was freely diffusible, ~6% was associated with the membrane, and ~37% was bound within the fiber. Under native zymography conditions, only 10% of MMP2 became active upon prolonged (17 h) exposure to 20 μM Ca2+, a concentration that would fully activate calpain-1 in seconds to minutes; full activation of MMP2 would require ~1 mM Ca2+. Given the prevalence of intracellular MMP2 in skeletal muscle, it is necessary to investigate its function using physiological conditions, including isolation of any potential functional relevance of MMP2 from that of the abundant protease calpain-1.
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Sultan, Baqur A., i Raad Ajam Sayhel Al.Jorany. "Evaluation of Matrix Metalloproteinase-2 (MMP2) in Aborted Women Infected with Toxoplasma gondii." Kufa Journal for Nursing Sciences 6, nr 2 (29.08.2016): 122–29. http://dx.doi.org/10.36321/kjns.vi20162.2704.
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Background: Toxoplasmosis is one of the most common zoonotic pathogens worldwide; Life cycle of this parasite was affected by synthesis of specific enzyme like Matrix metalloproteinase-2 (MMP2). Objectives: The major objectives of this study detection of prevalence expression of Matrix metalloproteinase-2 (MMP2) among ninety-six aborted women were tested; seventy-six of them was with recurrent abortions due to Toxoplasmosis and twenty without Toxoplasmosis as control group in Najaf governorate. Methodology: Descriptive case-control ,purposive (probability) sample among ninety six aborted women were tested, attending in Central Health Laboratory, Al-Zahra Maternity & pediatric Teaching Hospital , The data collected from January 2014 to January 2015. The concentration level of Matrix metalloproteinase-2 (MMP2) in aborted women was measured by ELISA technique according to many parameters such as age, occupation, residence and number of abortions. Results: The result indicated that the concentration of MMP2was elevated in women with one or two abortions. The high concentration of MMP2 in infected aborted women with age group (20-24), (25-29).there was significant differences in study groups according to occupation and there were differences in MMP2concentration levels according to residency. It was demonstrated that the high concentration of MMP2 was appear in rural infected aborted women and low in urban women with Toxoplasmosis, Results were analyzed by using statistical methods (Levene test, ANOVA test, t test). Conclusion: Matrix metalloproteinase-2(MMP2) play a significant role in immunity against infection with Toxoplasma gondii. Recommendation: Further studies are recommended to know the concentration of MMP2 among pregnant women to be one of an important laboratory tests in the induction of immune response against this type of infection.
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Kan, Taichi, Hiromi Ueda, Taishi Takahara, Yoshimasa Tsuchiya, Mayuko Kishimoto, Yasue Uchida, Tetsuya Ogawa, Wataru Ohashi, Toyonori Tsuzuki i Yasushi Fujimoto. "Association of Matrix Metalloproteinase-2 mRNA Expression with Subtypes of Pediatric Cholesteatoma". BioMed Research International 2021 (10.03.2021): 1–8. http://dx.doi.org/10.1155/2021/6644897.
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Objective. Cholesteatoma is a clinically heterogeneous disease, with some patients showing spontaneous regression, while others experiencing an aggressive, lethal disease. Cholesteatoma in children can be divided into two types: congenital and acquired. Identifying good prognostic markers is needed to help select patients who will require immediate surgical intervention. Matrix metalloproteinase-2 (MMP2) was previously reported to play an important role in cholesteatoma progression, by promoting bone destruction and keratinocyte infiltration. Herein, we analyzed MMP2 mRNA expression level in cholesteatoma using RNA-in situ hybridization in formalin-fixed, paraffin-embedded (FFPE) tissue samples. Methods. Sixty patients with cholesteatoma under 15 years old, who underwent their primary surgery at Aichi Medical University’s Otolaryngology Department, were analyzed for MMP2 expression level, using RNA-in situ hybridization. Results. There were no significant differences in MMP2 mRNA expression level between congenital cholesteatoma and acquired cholesteatomas. In congenital cholesteatoma, higher MMP2 signals were observed in the open type than in the closed type ( p < 0.001 ). In acquired cholesteatoma, higher MMP2 signals were observed in the pars tensa than in the pars flaccida ( p < 0.001 ). MMP2 mRNA expression level was almost exclusively found in the fibroblasts or in the inflammatory cells in the stroma, but not in the epithelium. Conclusion. Our study reveals that MMP2 mRNA expression level is strongly associated with the subtypes of cholesteatoma. The findings suggest that the level of expression of MMP2 mRNA may be related to the pathogenesis and aggressive features of cholesteatoma.
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Zhang, Jianmei, Mi-Yeon Kim i Jae Youl Cho. "Euodia pasteuriana Methanol Extract Exerts Anti-Inflammatory Effects by Targeting TAK1 in the AP-1 Signaling Pathway". Molecules 25, nr 23 (7.12.2020): 5760. http://dx.doi.org/10.3390/molecules25235760.
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Euodia pasteuriana A. Chev. ex Guillaumin, also known as Melicope accedens (Blume) T.G. Hartley, is a herbal medicinal plant native to Vietnam. Although Euodia pasteuriana is used as a traditional medicine to treat a variety of inflammatory diseases, the pharmacological mechanisms related to this plant are unclear. This study aimed to investigate the anti-inflammatory effects of a methanol extract of Euodia pasteuriana leaves (Ep-ME) on the production of inflammatory mediators, the mRNA expression of proinflammatory genes, and inflammatory signaling activities in macrophage cell lines. The results showed that Ep-ME strongly suppressed the release of nitric oxide (NO) in RAW264.7 cells induced with lipopolysaccharide (LPS), pam3CysSerLys4 (Pam3CSK), and polyinosinic-polycytidylic acid (poly I:C) without cytotoxicity. A reverse transcription-polymerase chain reaction further confirmed that Ep-ME suppressed the expression of interleukin 6 (IL-6), matrix metalloproteinase-1 (MMP1), matrix metalloproteinase-2 (MMP2), matrix metalloproteinase-3 (MMP3), tumor necrosis factor-α (TNF-α), and matrix metalloproteinase-9 (MMP9) at the transcriptional level and reduced the luciferase activities of activator protein 1 (AP-1) reporter promoters. In addition, immunoblotting analyses of the whole lysate and nuclear fraction, as well as overexpression assays demonstrated that Ep-ME decreased the translocation of c-Jun and suppressed the activation of transforming growth factor beta-activated kinase 1 (TAK1) in the AP-1 signaling pathways. These results imply that Ep-ME could be developed as an anti-inflammatory agent that targets TAK1 in the AP-1 signaling pathway.
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Yang, Zhantao, Themis R. Kyriakides i Paul Bornstein. "Matricellular Proteins as Modulators of Cell–Matrix Interactions: Adhesive Defect in Thrombospondin 2-null Fibroblasts is a Consequence of Increased Levels of Matrix Metalloproteinase-2". Molecular Biology of the Cell 11, nr 10 (październik 2000): 3353–64. http://dx.doi.org/10.1091/mbc.11.10.3353.
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Thrombospondin 2 (TSP2)-null mice, generated by disruption of theThbs2 gene, display a variety of connective tissue abnormalities, including fragile skin and the presence of abnormally large collagen fibrils with irregular contours in skin and tendon. In this study we demonstrate that TSP2-null skin fibroblasts show a defect in attachment to a number of matrix proteins, and a reduction in cell spreading. To investigate the molecular mechanisms responsible for these abnormal cell–matrix interactions, we compared the levels of matrix metalloproteinases (MMPs) in wild-type and mutant fibroblasts. Isolation and analysis of gelatinases from conditioned media by gelatin-agarose affinity chromatography and gelatinolytic assays demonstrated that TSP2-null fibroblasts produce a 2-fold increase in gelatinase A (MMP2) compared with wild-type cells. The adhesive defect was corrected by treatment of TSP2-null fibroblasts with soluble TSP2, with the MMP inhibitors BB94 and tissue inhibitor of metalloproteinase-2, and with a neutralizing antibody to MMP2. Moreover, stable transfection of TSP2-null fibroblasts with mouse TSP2 cDNA corrected both the adhesive defect and the altered expression of MMP2. Finally, MMP2 was shown to interact with TSP2 in a direct-binding plate assay. We conclude that TSP2 plays an important role in cell–matrix interactions, and that a deficiency in the protein results in increased levels of MMP2 that contribute to the adhesive defect in TSP2-null fibroblasts and could play a role in the complex phenotype of TSP2-null mice.
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Santiago-Ruiz, Buendía-Roldán, Pérez-Rubio, Ambrocio-Ortiz, Mejía, Montaño i Falfán-Valencia. "MMP2 Polymorphism Affects Plasma Matrix Metalloproteinase (MMP)-2 Levels, and Correlates with the Decline in Lung Function in Hypersensitivity Pneumonitis Positive to Autoantibodies Patients." Biomolecules 9, nr 10 (5.10.2019): 574. http://dx.doi.org/10.3390/biom9100574.
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Among hypersensitivity pneumonitis (HP) patients have been identified who develop autoantibodies with and without clinical manifestations of autoimmune disease. Genetic factors involved in this process and the effect of these autoantibodies on the clinical phenotype are unknown. Matrix metalloproteinases (MMPs) have an important role in architecture and pulmonary remodeling. The aim of our study was to identify polymorphisms in the MMP1, MMP2, MMP9 and MMP12 genes associated with susceptibility to HP with the presence of autoantibodies (HPAbs+). Using the dominant model of genetic association, comparisons were made between three groups. For rs7125062 in MMP1 (CC vs. CT+TT), we found an association when comparing groups of patients with healthy controls: HPAbs+ vs. HC (p < 0.001, OR = 10.62, CI 95% = 4.34 − 25.96); HP vs. HC (p < 0.001, OR = 7.85, 95% CI 95% = 4.54 − 13.57). This rs11646643 in MMP2 shows a difference in the HPAbs+ group by the dominant genetic model GG vs. GA+AA, (p = 0.001, OR = 8.11, CI 95% = 1.83 − 35.84). In the linear regression analysis, rs11646643 was associated with a difference in basal forced vital capacity (FVC)/12 months (p = 0.013, = 0.228, 95% CI95% = 1.97 − 16.72). We identified single-nucleotide polymorphisms (SNPs) associated with the risk of developing HP, and with the evolution towards the phenotype with the presence of autoantibodies. Also, to the decrease in plasma MMP-2 levels.
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Jiang, Wenhong, Zhanman Zhang, Han Yang, Qiuning Lin, Chuangye Han i Xiao Qin. "The Involvement of miR-29b-3p in Arterial Calcification by Targeting Matrix Metalloproteinase-2". BioMed Research International 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/6713606.
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Vascular calcification is a risk predictor and common pathological change in cardiovascular diseases that are associated with elastin degradation and phenotypic transformation of vascular smooth muscle cells via gelatinase matrix metalloproteinase-2 (MMP2). However, the mechanisms involved in this process remain unclear. In this study, we investigated the relationships between miR-29b-3p and MMP2, to confirm miR-29b-3p-mediated MMP2 expression at the posttranscriptional level in arterial calcification. In male Sprague Dawley rats, arterial calcification was induced by subcutaneous injection of a toxic dose of cholecalciferol. In vivo, the quantitative real-time polymerase chain reaction (qRT-PCR) showed that MMP2 expression was upregulated in calcified arterial tissues, and miR-29b-3p expression was downregulated. There was a negative correlation between MMP2 mRNA expression and miR-29b-3p levels (P=0.0014,R2=0.481). Western blotting showed that MMP2 expression was significantly increased in rats treated with cholecalciferol. In vitro, overexpression of miR-29b-3p led to decreased MMP2 expression in rat vascular smooth muscle cells, while downregulation of miR-29b-3p expression led to increased MMP2 expression. Moreover, the luciferase reporter assay confirmed that MMP2 is the direct target of miR-29b-3p. Together, our results demonstrated that a role of miR-29b-3p in vascular calcification involves targeting MMP2.
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Tabouret, Emeline, Francoise Boudouresque, Jaime Callego Perez-Larraya, Maryline Barrie, Giuseppe Lombardi, Mona Matta, Anna Luisa Di Stefano i in. "Association of matrix metalloproteinase 2 (MMP2) baseline plasma level to objective response (OR), progression free survival (PFS), and overall survival (OS) and changes under treatment in patients treated with bevacizumab (Bev) for recurrent high-grade glioma (HGG)." Journal of Clinical Oncology 31, nr 15_suppl (20.05.2013): 2024. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2024.
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2024 Background: Predictive marker of Bev activity is an unmet medical need. We evaluated predictive value of selected circulating prebiomarkers involved in neoangiogenesis and invasion on patient outcome in recurrent HGG treated with Bev. Methods: A set of eleven prebiomakers of interest (VEGF, VEGF-R2, bFGF, SDF1, PlGF, uPA, PAI1, MMP2, MMP7, MMP9, and adrenomedulline) were analyzed in plasma, using ELISA, at baseline from Bev initiation in a prospective cohort of 26 patients (Cohort1). Correlations were validated in a separate retrospective Bev treated cohort (Cohort2; n = 50) and then tested in a cohort of patients treated with cytotoxic agents without Bev (Cohort3; n = 34). Dosages were correlated to OR, PFS, and OS. MMP2 and MMP9 were then analyzed at multiple time points up to progression. Results: In cohort1, high MMP2 baseline level was associated with an OR rate of 83.3% for high levels versus 15.4% for low MMP2 levels (p = 0.001). In multivariate analysis, MMP2 baseline level was correlated with PFS (hazard-ratio (HR), 3.92; 95% confidence-interval (CI):1.46-10.52; p = 0.007) and OS (HR, 4.62; 95%CI 1.58-13.53; p = 0.005), as MMP9 (p = 0.016 for PFS and p = 0.025 for OS). Similar results were found in cohort2 for MMP2, (MMP2: p<0.001 for OR; p = 0.009 for PFS; p = 0.009 for OS) but not for MMP9. In cohort3, no association was found between MMP2, MMP9 and outcome. Significant changes in MMP2 and MMP9 plasma levels were observed during treatment. MMP2 increased after Bev initiation (p = 0.002), and decreased at progression (p = 0.002) while MMP9 initially decreased (p = 0.007) then increased at progression (p = 0.031). Conclusions: In patients with recurrent HGG treated with bevacizumab, but not with cytotoxic agents, high MMP2 plasma levels are associated with prolonged tumor control and survival while changes over time may reflect tumor control. MMP2 should be tested in randomized clinical trials that evaluate bevacizumab efficacy, and its biological role should be reassessed.
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Chen, Guobing, Dandan Ge, Bizhen Zhu, Huixuan Shi i Qilin Ma. "Upregulation of matrix metalloproteinase 9 (MMP9)/tissue inhibitor of metalloproteinase 1 (TIMP1) and MMP2/TIMP2 ratios may be involved in lipopolysaccharide-induced acute lung injury". Journal of International Medical Research 48, nr 4 (kwiecień 2020): 030006052091959. http://dx.doi.org/10.1177/0300060520919592.
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Objective This study aimed to examine the changes and significance of matrix metalloproteinase 9 (MMP9), MMP2, tissue inhibitor of metalloproteinase 1 (TIMP1), and TIMP2 in rats with lipopolysaccharide (LPS)-induced acute lung injury (ALI). Methods Wistar rats were randomly divided into a control group (injected with saline) and an ALI group (injected with LPS), then subdivided into four time points (2, 6, 12, and 24 hours). Serum tumor necrosis factor alpha and interleukin-6 levels were detected by ELISA to investigate the inflammatory reaction after LPS injection. The degree of ALI was determined by hematoxylin–eosin staining of lung tissue, the lung wet/dry weight ratio, and pulmonary permeability index. Changes in lung MMP and TIMP protein and mRNA levels were detected by western blotting and quantitative real-time polymerase chain reaction. Results Changes in the ratios of MMP9/TIMP1 and MMP2/TIMP2 were consistent with and strongly positively associated with the lung wet/dry weight ratio, the pulmonary permeability index, and serum tumor necrosis factor alpha and interleukin-6 levels in the ALI group. Conclusion ALI induced by LPS may be related to upregulation of MMP9/TIMP1 and MMP2/TIMP2 ratios.
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Balode, Evija, i Mara Pilmane. "Characteristics of Neuropeptide-Containing Innervation, Tissue Remodeling, Growth, and Vascularity in Noses of Patients With Cleft Lip and Palate". Cleft Palate-Craniofacial Journal 57, nr 8 (18.02.2020): 948–56. http://dx.doi.org/10.1177/1055665620904519.
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Objective: To detect the appearance and distribution of factors regulating remodeling, innervation, growth, and vascularity of the nasal tissue affected by cleft lip and palate (CLP). Design: Morphological analysis of human tissue. Setting: Cleft and craniofacial center. Participants: Fifteen patients who underwent CLP rhinoplasty, 7 control patients. Interventions: Rhinoplasty. Main Outcome Measures: Immunohistochemistry was performed with protein gene product (PGP) 9.5, transforming growth factor β1 (TGFβ1), vascular endothelial growth factor (VEGF), cluster of differentiation 34 (CD34), matrix metalloproteinase 2 (MMP2), MMP9, and tissue inhibitor of metalloproteinase 2 (TIMP2). The results were evaluated semiquantitatively. Spearman rank order correlation coefficient and Mann-Whitney U test were used for statistical analysis. Results: Cleft lip and palate–affected tissue revealed dense and loose connective tissue, adipose cells, and hyaline cartilage, along with numerous CD34-positive endotheliocytes and regions of VEGF-positive neoangiogenesis. We observed moderate to numerous PGP 9.5-positive nerve fibers. Transforming growth factor β1, MMP2, MMP9, and TIMP2 were found in cartilage and connective tissue. Cleft lip and palate–affected tissue compared to control samples showed a statistically significant difference in PGP 9.5 ( P = .006), VEGF ( P = .001), MMP2 ( P = .002), MMP9 ( P = .013), and TIMP2 ( P < .001) expression. We observed a strong, positive correlation between VEGF and MMP9 ( P = .027; r S = 0.705). Conclusions: The moderate expression of TGFβ1 and increased distribution of VEGF, MMP2, MMP9, and TIMP2 demonstrate an active extracellular matrix remodeling and angiogenesis, performed by proteases. The cartilaginous septum of the nose is an example of balance between tissue degradation and its suppression, demonstrated by the relationship between MMPs and TIMPs and the presence of VEGF.
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Ranjbaran, Javad, Marzieh Farimani, Heidar Tavilani, Marzieh Ghorbani, Jamshid Karimi, Faranak Poormonsefi i Iraj Khodadadi. "Matrix metalloproteinases 2 and 9 and MMP9/NGAL complex activity in women with PCOS". REPRODUCTION 151, nr 4 (kwiecień 2016): 305–11. http://dx.doi.org/10.1530/rep-15-0340.
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It is believed that matrix metalloproteinases (MMPs) play important roles in follicular development and pathogenesis of polycystic ovary syndrome (PCOS). However, conflicting results are available about the alteration of MMP2 and MMP9 concentrations or activities in PCOS. In fact, there is no study entirely investigating both concentration and activity of these MMPs and serum levels of their tissue inhibitors TIMP2 and TIMP1, as well as lipocalin-bound form of MMP9 (MMP9/NGAL). Therefore, the thoroughness of previous studies is questionable. This study was conducted to determine circulatory concentration of MMP2, MMP9, MMP9/NGAL complex, TIMP1 and TIMP2 as well as gelatinase activities of MMP2, MMP9 and MMP9/NGAL complex in women with PCOS and controls. Mean age and BMI as well as serum levels of total cholesterol, triacylglycerol, HDL-C, LDL-C, fasting blood sugar (FBS), insulin, estradiol and sex hormone-binding globulin did not differ between groups, whereas a marked decrease in FSH and significant increases in LH, LH/FSH ratio, testosterone and free androgen index were observed. Women with PCOS and controls showed closed concentrations of MMP2, MMP9, MMP9/NGAL, TIMP1 and TIMP2. Gelatinase activity of MMP9 was found significantly higher in PCOS than in controls (64.53±15.32 vs 44.61±18.95 respectively) while patients and healthy subjects showed similar activities of MMP2 and MMP9/NGAL complex. Additionally, PCOS patients showed a higher MMP9/TIMP1 ratio compared with control women. Direct correlations were also observed between circulatory MMP9 level and the concentration and activity of MMP9/NGAL complex. In conclusion, based on the results of present study, we believe that MMP9 may be involved in the pathogenesis of PCOS.
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Liu, G., M. Fruh, W. Zhou, R. Zhai, L. Su, R. S. Heist, J. C. Wain, T. J. Lynch, F. A. Shepherd i D. C. Christiani. "Matrix metalloproteinase 2 (MMP2) polymorphism, Helicobacter pylori (HP) infection and esophageal adenocarcinoma (EA) risk". Journal of Clinical Oncology 25, nr 18_suppl (20.06.2007): 10553. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.10553.
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10553 Background: Epidemiologic studies suggest that HP infection protects against EA risk, as HP-mediated chronic atrophic gastritis reduces acid reflux. Genetic variations may modify the host response to HP infection and alter this risk. MMP2 expression is commonly upregulated in HP infections. We hypothesize that a functional MMP2 promoter polymorphism (-C1306T) that abolishes a Sp1 binding site and decreases promoter activity will also reduce the protective effects of HP infections in EA risk. Methods: HP status was determined in 98 EA patients and 101 age and gender matched healthy controls, using a commercially available serum immunoblotting kit (Helicoblot 2.1, Genelabs Diagnostics) that measures ever, current, CagA+ and VacA+ HP infections. Genotyping was performed using TaqMan. Data were analyzed using unconditional logistic regression. Results: 39% of cases and 44% of controls (P=0.69) had MMP2 variants (T/T or C/T). 36% of cases and 42% of controls were ever HP infected (P= 0.35). In individuals carrying the MMP2 wild type (CC) genotype, ever HP infection was strongly protective against EA [Odds Ratio (OR) 0.32: 95% CI, 0.13–0.75; P=0.008]. In contrast, in individuals carrying the MMP2 variants that are associated with lower promoter activity, this protective effect was lost (OR 1.76; 95% CI, 0.06–5.2; P= 0.30). Similar results were found when evaluating the MMP2 and current, CagA or VacA infection. Statistical interactions between MMP2 genotype and ever HP infection (P=0.027) and between MMP2 genotype and VacA+ infection (P= 0.035) were significant. Conclusions: We are the first to report that host factors such as the MMP2 polymorphism modulate the role of HP infection in EA susceptibility. No significant financial relationships to disclose.
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Zhang, Yulei, i Xiaoqin Chen. "lncRNA FOXD2-AS1 affects trophoblast cell proliferation, invasion and migration through targeting miRNA". Zygote 28, nr 2 (13.01.2020): 131–38. http://dx.doi.org/10.1017/s0967199419000807.
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SummaryThe abnormal expression of lncRNAs and miRNAs has been found in the placentas of patients with preeclampsia (PE). Therefore, we determined the role of lncRNA FOXD2-AS1/miR-3127 in trophoblast cells. The expression of lncRNA FOXD2-AS1 was detected by qRT-PCR. The proliferation, migration and invasion ability of trophoblast cells were evaluated using CCK-8, wound healing and transwell assays. The target gene of lncRNA FOXD2-AS1 was determined by StarBase and luciferase reporter assays. Western blotting was used to analyze the expression of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9). The results showed that FOXD2-AS1 affected trophoblast cell viability in vitro, while the expression of miR-3127 was decreased. FOXD2-AS1 silencing decreased the promotion effects on trophoblast cell induced by miR-3127 inhibition. In addition, FOXD2-AS1 and miR-3127 presented the same effect on MMP2 and MMP9 levels. lncRNA FOXD2-AS1 modulated trophoblast cell proliferation, invasion and migration through downregulating miR-3127 expression. Therefore, lncRNA FOXD2-AS1 could act as a latent therapeutic marker in preeclampsia.
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Pustovrh, M. C., A. Jawerbaum, V. White, E. Capobianco, R. Higa, N. Martínez, J. J. López-Costa i E. González. "The role of nitric oxide on matrix metalloproteinase 2 (MMP2) and MMP9 in placenta and fetus from diabetic rats". Reproduction 134, nr 4 (październik 2007): 605–13. http://dx.doi.org/10.1530/rep-06-0267.
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Matrix metalloproteinases (MMPs) play an important role in tissue remodeling that accompanies the rapid growth, differentiation, and structural changes of the placenta and several fetal organs. In the present study, we investigated whether the diabetic maternal environment may alter the regulatory homeostasis exerted by nitric oxide (NO) on MMPs activity in the feto-placental unit from rats at midgestation. We found that NADPH-diaphorase activity, which reflects the distribution and activity of NO synthases (NOS), was increased in both placenta and fetuses from diabetic rats when compared with controls. In addition, while a NO donor enhanced MMP2 and MMP9 activities, a NOS inhibitor reduced these activities in the maternal side of the placenta from control rats. This regulatory effect of NO was only observed on MMP9 in the diabetic group. On the other hand, the NO donor did not modify MMP2 and MMP9 activities, while the NOS inhibitor reduced MMP9 activity in the fetal side of both control and diabetic placentas. In the fetuses, MMP2 was enhanced by the NO donor and reduced by the NO inhibitor in both fetuses from control and diabetic rats. Overall, this study demonstrates that NO is able to modulate the activation of MMPs in the feto-placental unit, and provides supportive evidence that increased NOS activity leads to NO overproduction in the feto-placental unit from diabetic rats, an alteration closely related to the observed MMPs dysregulation that may have profound implications in the formation and function of the placenta and the fetal organs.
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Kumar N, Dr Kiran, Dr B. Brigit, Dr Saranya Ramachandran, Dr Savitha B Naik, Dr Seema Merwade i Dr Swathi K. "Correlation Between Salivary Levels of Matrix Metalloproteinases 2,9 and Caries Incidence in An Indian Population". RGUHS Journal of Dental Sciences 12, nr 1 (2020): 44–48. http://dx.doi.org/10.26715/rjds.12_1_9.
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Aim: To evaluate the salivary Matrix metalloproteinases 2 and Matrix metalloproteinase 9 activity in participants with high caries index and to compare it with that of caries free participants. Materials and Methods: Unstimulated salivary samples of 100 high and low caries index participants were collected within the age group of 18-60. The mean pH of all the samples was tested with a pH meter. The activity of Matrix metalloproteinases 2 and 9 was determined using gelatin zymography. Result: Mean salivary pH of high caries index participants were significantly higher than that of caries free participants. Also,gelatinase activity determined using gelatin zymography was significantly higher in the salivary samples of the participants with high caries index than that of the low caries index participants. Conclusion: Salivary MMP2 and MMP9 was determined to be more active in high caries index participants saliva than that of caries free participants. Thus, this was predictive of the enhanced activity of MMP 2 and MMP 9 which are gelatinases. This directs towards the significance of MMP 2 and MMP 9’s role in the degradation of dentine collagen matrix and thereby caries progression.
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Liu, Jiangwei, Xiaocheng Li, Jianzhao Huang i Yan Liu. "Matrix metalloproteinase 2 knockdown suppresses the proliferation of HepG2 and Huh7 cells and enhances the cisplatin effect". Open Medicine 14, nr 1 (17.05.2019): 384–91. http://dx.doi.org/10.1515/med-2019-0039.
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AbstractBackgroundThis study evaluated the functions of matrix metalloproteinase 2 (MMP2) in hepatocellular carcinoma (HCC) cells and assessed the effects of MMP2 on HCC cell sensitivity to cisplatin.MethodologyHepG2 and Huh7 cells were cultured. A pre-experiment was performed to explore the optimal transduction conditions of the MMP2-siRNA lentivirus (si-MMP2). Quantitative real-time PCR and western blot assays were performed to measure the expression levels of MMP2 in HepG2 and Huh7 cells. An MTT assay was used to evaluate cell proliferation, and flow cytometry analysis was applied to examine cell apoptosis. A Transwell assay was carried out to assess cell invasion.ResultsThe optimal virus:cell ratio was 100 multiplicity of infection (MOI) for both cells, and the optimal transduction times for HepG2 and Huh7 cells were 48 h and 72 h, respectively. MMP2 knockdown significantly decreased the mRNA and protein levels of MMP2 in both cell lines (P<0.01). MMP2 knockdown significantly decreased the proliferation and increased the apoptosis of HepG2 and Huh7 cells (P<0.01). Co-treatment with si-MMP2 and cisplatin significantly increased the sensitivity of HepG2 and Huh7 cells to cisplatin (P<0.01).ConclusionMMP2 may act as an oncogene and may be a potential therapeutic target in HCC.
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Diebold, Isabel, Andreas Petry, Maximilian Burger, John Hess i Agnes Görlach. "NOX4 mediates activation of FoxO3a and matrix metalloproteinase-2 expression by urotensin-II". Molecular Biology of the Cell 22, nr 22 (15.11.2011): 4424–34. http://dx.doi.org/10.1091/mbc.e10-12-0971.
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The vasoactive peptide urotensin-II (U-II) has been associated with vascular remodeling in different cardiovascular disorders. Although U-II can induce reactive oxygen species (ROS) by the NADPH oxidase NOX4 and stimulate smooth muscle cell (SMC) proliferation, the precise mechanisms linking U-II to vascular remodeling processes remain unclear. Forkhead Box O (FoxO) transcription factors have been associated with redox signaling and control of proliferation and apoptosis. We thus hypothesized that FoxOs are involved in the SMC response toward U-II and NOX4. We found that U-II and NOX4 stimulated FoxO activity and identified matrix metalloproteinase-2 (MMP2) as target gene of FoxO3a. FoxO3a activation by U-II was preceded by NOX4-dependent phosphorylation of c-Jun NH(2)-terminal kinase and 14-3-3 and decreased interaction of FoxO3a with its inhibitor 14-3-3, allowing MMP2 transcription. Functional studies in FoxO3a-depleted SMCs and in FoxO3a–/– mice showed that FoxO3a was important for basal and U-II–stimulated proliferation and vascular outgrowth, whereas treatment with an MMP2 inhibitor blocked these responses. Our study identified U-II and NOX4 as new activators of FoxO3a, and MMP2 as a novel target gene of FoxO3a, and showed that activation of FoxO3a by this pathway promotes vascular growth. FoxO3a may thus contribute to progression of cardiovascular diseases associated with vascular remodeling.
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Sperone, P., M. Volante, A. Berruti, E. Bollito, E. Frangipane, F. Daffara, M. Terzolo, G. Gorzegno, L. Dogliotti i M. Papotti. "Matrix metalloproteinase type 2 (MMP2) is selective expressed in adrenocortical carcinoma but not in adrenal adenoma: An immunohistochemical study". Journal of Clinical Oncology 24, nr 18_suppl (20.06.2006): 14534. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.14534.
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14534 Background: Adrenocortical carcinoma (ACC) is a very rare disease which account for no more than 0.2% of all malignancies, and its differential diagnosis from adrenocortical adenomas (ACA) is based on the application of different scoring systems, which, however, lack a sensitivity and specificity of 100%. Little is known on the mechanisms leading to the malignant phenotype in adrenocortical tumors; among alternative mechanisms, metalloproteinases (MMPs) have been demonstrated in solid tumors, including endocrine ones, to be implicated in malignant progression and metastatization. Our aim was to investigate metalloproteinase 2 (MMP2) expression in adrenocortical tumors. Methods: A series of 33 ACC and 23 ACA was retrospectively collected from a large series of adrenocortical lesions, and the diagnosis was reviewed independently by three investigators (MV, EB, MP) according to the Weiss histological criteria. MMP2 was determined by immunohistochemistry and the results scored by semi-quantitative analysis, based on the intensity of the staining and the percentage of tumor cells positive. Immunohistochemical results were compared to clinico-pathological parameters, such as sex, age, hormonal secretion, and outcome. Results: MMP2 expression was detected in 1/23 ACA (4%), and in 25/33 ACC (76%) (X-square test p < 0.001). MMP2 immunohistochemical pattern in ACC was focal to moderate to strong in 10, 12 and 3 cases, respectively. In addition, moderate to strong MMP2 expression, as compared to low or negative immunostaining, correlated with shorter disease-free survival (p = 0.012) and poor outcome (p = 0.07). No correlation were found comparing MMP2 expression and other clinico-pathological parameters. Conclusions: As reported in a variety of solid tumors, our data indicates a possible role of MMP2 in the malignant evolution of adrenocortical tumors, and its immunohistochemical localization may be a potential useful tool in the differential diagnosis of benign versus malignant adrenocortical lesions. In addition, a strong immunohistochemical MMP2 expression seems to be related to a poor prognosis in ACC. No significant financial relationships to disclose.
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LEGALLICIER, BRUNO, GERMAIN TRUGNAN, GILLIAN MURPHY, BRIGITTE LELONGT i PIERRE RONCO. "Expression of the Type IV Collagenase System during Mouse Kidney Development and Tubule Segmentation". Journal of the American Society of Nephrology 12, nr 11 (listopad 2001): 2358–69. http://dx.doi.org/10.1681/asn.v12112358.
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Abstract. Type IV collagenases matrix metalloproteinase-2 (MMP2) and MMP9 and their related proteins, MT1-MMP, tissue inhibitor of metalloproteinases 1 (TIMP1), TIMP2, and TIMP3, are expressed during kidney morphogenesis and nephrogenesis, but the renal ontogeny of these proteins is only partially known, and their persistence in the adult remains controversial. Their expression was analyzed from early metanephric stages to adulthood by Western blot semiquantitative analysis; laser confocal microscopy of whole-mount kidneys; and a two-step immunoperoxidase labeling procedure using specific markers of proximal tubule (megalin), ascending limb of Henle's loop (Tamm Horsfall protein), and collecting duct (Dolichos biflorusagglutinin lectin). By Western blot, all antigens were detected at day 11.5, peaked at day 16.5, and persisted in the adult at lower levels, although MMP2 was less modulated. All antigens were expressed in metanephric mesenchyme at embryonic day 11.5 and became concentrated in neural cell adhesion molecule-positive—induced mesenchymal cells at day 12.5. Only MT1-MMP and to a lesser extent MMP2 were detected in the ureter bud. At day 16.5, all antigens predominated in the cytoplasm of the proximal tubule, except TIMP1, which was mostly expressed in the ascending limb of Henle's loop and distal tubule. During tubule segmentation, components of the type IV collagenase system showed both spatial and temporal regulation. The distribution of gelatinases was not strictly superimposable to that of their natural inhibitors TIMP, especially for MMP9 and TIMP1. All components persisted in specific segments of the adult renal tubule, where MMP9, MMP2, and MT1-MMP showed an apical expression, suggesting that substrates for these enzymes should be in the tubule lumen or in the apical cell domain and not in the extracellular matrix. These results suggest that a regulated balance of gelatinase activity is required during kidney organogenesis and that gelatinases continue to play a role in adult renal tubule physiology.
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Pustovrh, Carolina, Alicia Jawerbaum, Débora Sinner, Verónica White, Evangelina Capobianco i Elida González. "Metalloproteinase 2 activity and modulation in uterus from neonatal streptozotocin-induced diabetic rats during embryo implantation". Reproduction, Fertility and Development 14, nr 8 (2002): 479. http://dx.doi.org/10.1071/rd02001.
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Matrix metalloproteinases (MMPs) are responsible for the remodelling of the uterine extracellular matrix during embryo implantation. Nitric oxide (NO) production is increased at the time when implantation begins. Abnormal tissue levels of MMPs are present in diabetes; elevated NO levels in tissues and an increased oxidative stress are also found. The present work evaluates the uterine MMP2 activity and levels during embryo implantation, as well as the influence of nitridergic compounds and reactive oxygen species (ROS) on the MMP2 enzymatic activity in a model of neonatal streptozotocin-induced diabetic rat. Metalloproteinase 2 activity and levels are increased in diabetic tissues compared with controls (P<0.05 and P<0.002 respectively). The uterine enzymatic activity in diabetic animals decreases in the presence of the NOS inhibitor NG-nitro-L-arginine methyl ester (P<0.01) and is enhanced (P<0.005) when a generating ROS system (xanthine/xanthine oxidase) is added to the incubating medium. It was also found that uterine superoxide dismutase activity is higher in diabetic rats than in control rats on the day of implantation (P<0.001), suggesting a compensatory antioxidant ability. In conclusion, the results show that the uterine MMP2 activity, which is higher in diabetic animals than in control animals, is modulated positively by NO and ROS during embryo implantation in a model of streptozotocin-induced diabetic rats.
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Li, Ying, Qing-rong Ouyang, Juan Li, Xiao-rong Chen, Lin-lin Li, Lei Xu i Ming Yu. "Correlation between matrix metalloproteinase-2 polymorphisms and first and recurrent atherosclerotic ischemic stroke events: a case–control study". Journal of International Medical Research 49, nr 6 (czerwiec 2021): 030006052110229. http://dx.doi.org/10.1177/03000605211022967.
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Objective To determine the associations between matrix metalloproteinase-2 (MMP-2, encoded by the MMP2 gene) 1306C/T and 735C/T polymorphisms and first and recurrent ischemic stroke in a Chinese population. Methods Patients with first and recurrent ischemic stroke were included. Serum MMP-2 was measured, and MMP2 1306C/T and 735C/T polymorphisms were detected. The associations between MMP2 1306C/T and 735C/T polymorphisms and first and recurrent ischemic stroke were analyzed. Results Serum MMP-2 in patients with first and recurrent ischemic stroke was significantly higher compared with controls, and patients with recurrent ischemic stroke had higher MMP-2 than those with first ischemic stroke. The frequency of the CC genotype and C allele of MMP2 735C/T was highest in patients with recurrent ischemic stroke, followed by patients with first ischemic stroke, and controls. Conversely, the genotype and allele of MMP2 1306C/T did not significantly differ between groups. The CC genotype of MMP2 735C/T was independently associated with first and recurrent ischemic stroke (odds ratios = 1.45 and 1.64, respectively), as was the C allele of MMP2 735C/T (odds ratios = 1.68 and 1.77, respectively). Conclusions The CC genotype and C allele of MMP2 735C/T were associated with first and recurrent ischemic stroke in a Chinese population.
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Ren, Xiaoyu, Hongyang Xu, Robert G. Barker, Graham D. Lamb i Robyn M. Murphy. "Elevated MMP2 abundance and activity in mdx mice are alleviated by prenatal taurine supplementation". American Journal of Physiology-Cell Physiology 318, nr 6 (1.06.2020): C1083—C1091. http://dx.doi.org/10.1152/ajpcell.00437.2019.
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Duchenne muscular dystrophy (DMD) is a severe, progressive muscle-wasting disorder that leads to early death. The mdx mouse is a naturally occurring mutant model for DMD. It lacks dystrophin and displays peak muscle cell necrosis at ~28 days (D28), but in contrast to DMD, mdx mice experience muscle regeneration by D70. We hypothesized that matrix metalloproteinase-2 (MMP2) and/or MMP9 play key roles in the degeneration/regeneration phases in mdx mice. MMP2 abundance in muscle homogenates, measured by calibrated Western blotting, and activity, measured by zymogram, were lower at D70 compared with D28 in both mdx and wild-type (WT) mice. Importantly, MMP2 abundance was higher in both D28 and D70 mdx mice than in age-matched WT mice. The higher MMP2 abundance was not due to infiltrating macrophages, because MMP2 content was still higher in isolated muscle fibers where most macrophages had been removed. Prenatal supplementation with the amino acid taurine, which improved muscle strength in D28 mdx mice, produced approximately twofold lower MMP2 activity, indicating that increased MMP2 abundance is not required when muscle damage is attenuated. There was no difference in MMP9 abundance between age-matched WT and mdx mice ( P > 0.05). WT mice displayed decreased MMP9 abundance as they aged. While MMP9 may have a role during age-related skeletal muscle growth, it does not appear essential for degeneration/regeneration cycles in the mdx mouse. Our findings indicate that MMP2 plays a more active role than MMP9 in the degenerative phases of muscle fibers in D28 mdx mice.
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Silva, Juneo F., Natália M. Ocarino i Rogéria Serakides. "Spatiotemporal expression profile of proteases and immunological, angiogenic, hormonal and apoptotic mediators in rat placenta before and during intrauterine trophoblast migration". Reproduction, Fertility and Development 29, nr 9 (2017): 1774. http://dx.doi.org/10.1071/rd16280.
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The gene and/or protein expression of proteases and immunological, angiogenic, hormonal and apoptotic mediators was evaluated in rat placenta before and during intrauterine trophoblast migration. The depth of interstitial and endovascular intrauterine trophoblast invasion and the immunohistochemical expression of vascular endothelial growth factor (VEGF), fetal liver kinase 1 (Flk1), interferon (IFN)-γ, migration inhibitory factor (MIF), and inducible nitric oxide synthase (iNOS; also known as nitric oxide synthase (NOS) 2) were evaluated. In addition, the expression of the Vegf, Flk1, placental growth factor (Pigf), soluble fms-like tyrosine kinase 1 (sFlt1), placental lactogen 1 (Pl1), proliferin-related protein (rPlf), placental leptin (Lep), Toll-like receptor 2 (Tlr2), Toll-like receptor 4 (Tlr4), Infg, Mif, tumour necrosis factor-α (Tnf), interleukin-10 (Il10), Nos2, caspase 3 (Casp3), Bax, Bcl2, matrix metalloproteinase 2 (Mmp2) and matrix metalloproteinase 9 (Mmp9) genes was determined by real-time reverse transcription–polymerase chain reaction. At 10 days gestation, gene expression of Tlr2, Tlr4, Tnf, Infg, Il10, Casp3, Pigf, sFlt1 and Lep (P < 0.05) were higher than at 14 and/or 19 days of gestation. The beginning of intrauterine trophoblast invasion, i.e., at 14 days of gestation, coincided with higher gene and/or protein expression of MMP9, VEGF, Flk1, NOS2, MIF, BAX and rPlf compared to days 10 and 19 (P < 0.05). In contrast, gene expression of Mmp2 and Pl1 was higher at the end of trophoblast invasion compared to 10 and 14 days of gestation (P < 0.05). In conclusion, before intrauterine trophoblast migration, expression of TLRs and immunological and pro-apoptotic mediators is higher, whereas the beginning of trophoblast migration is characterised by higher expression of the pro-angiogenic factors NOS2 and MMP9. In contrast, MMP2 and PL1 expression is higher at the end of intrauterine trophoblast migration.
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Costanzo, Louis, Brian Soto, Richard Meier i Patrick Geraghty. "The Biology and Function of Tissue Inhibitor of Metalloproteinase 2 in the Lungs". Pulmonary Medicine 2022 (31.12.2022): 1–12. http://dx.doi.org/10.1155/2022/3632764.
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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.
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Chen, Qiuqiu, Min Pan, Yusong Lu, Feifei Wei, Chunqiao Chen i Hui Huang. "Proliferation, Metastasis, and Radiosensitivity of Nasopharyngeal Carcinoma Cells in the Expression and Effect of Kiwifruit Extract through the Regulation of miR-205-5p". Journal of Oncology 2022 (11.08.2022): 1–7. http://dx.doi.org/10.1155/2022/6925772.
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Background. Radix Actinidiae extract (RAE) has been shown to inhibit cancer in many studies, but its potential mechanism in nasopharyngeal cancer (NPC) progression remains unclear. Methods. NPC cells (SUNE1) were treated with different doses of RAE. For transfection, SUNE1 cells were transfected with the microRNA (miR)-205-5p inhibitor (anti-miR-205-5p) or mimic followed by treatment with 200 μg/mL RAE for 24 h. The MTT assay and colony formation assay were used to detect cell proliferation and radiosensitivity. The transwell assay was used to detect cell migration and invasion. The expression of miR-205-5p was detected by quantitative real-time PCR. The protein expression levels of matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-9 (MMP9) were detected by western blot analysis. Results. RAE inhibited NPC cell proliferation, migration, and invasion, while it enhanced radiosensitivity ( P < 0.05 ). Also, RAE treatment decreased miR-205-5p expression, as well as MMP2 and MMP9 protein levels ( P < 0.05 ). Anti-miR-205-5p transfection enhanced the effects of RAE on NPC cell proliferation, migration, invasion, and radiosensitivity ( P < 0.05 ), while miR-205-5p mimic transfection had an opposite effect ( P < 0.05 ). Conclusion. RAE might decrease miR-205-5p, thereby it inhibited NPC cell proliferation and metastasis and enhanced radiosensitivity.
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Wieczorek, Edyta, Michal Galicki, Bartlomiej Tomasik, Magdalena Krol, Ewa Jablonska, Wojciech Fendler, Jolanta Gromadzinska, Zbigniew Morawiec, Wojciech Wasowicz i Edyta Reszka. "Expression of MMP and TIMP mRNA in Peripheral Blood Leukocytes of Patients with Invasive Ductal Carcinoma of the Breast". International Journal of Biological Markers 31, nr 3 (lipiec 2016): 309–16. http://dx.doi.org/10.5301/jbm.5000203.
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Purpose An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) appears critical for tumor progression and metastasis. This study aimed to determine whether gene expression of MMP1, MMP2, MMP9, TIMP1 and TIMP3 and the MMP/TIMP expression ratio in peripheral blood leukocytes (PBLs) and the MMP1 and TIMP1 contents or MMP1/TIMP1 ratio in plasma were associated with clinicopathological characteristics in invasive ductal carcinoma (IDC) of the breast. Materials and methods Blood samples were collected from women newly diagnosed with IDC who had not received prior treatment (n = 102). Gene expression in PBLs was analyzed by quantitative real-time polymerase chain reaction. Concentrations of MMP1 and TIMP1 in plasma were measured using ELISA. Results In univariate analysis the expression levels of MMP2 and TIMP1 mRNA were significantly higher in premenopausal compared to postmenopausal patients (p<0.001 and p = 0.014, respectively). MMP2 mRNA expression negatively correlated with age (p<0.001, r = -0.43). We found that the MMP2/TIMP3 expression ratio was significantly higher in women after menopause (p = 0.007). The MMP2/TIMP1 expression ratio was higher in human epidermal growth factor receptor 2 (HER2)-positive patients (p = 0.022). Low-grade tumors had significantly lower MMP1/TIMP1 and MMP2/TIMP1 expression ratios (p = 0.047 and p = 0.048, respectively). TIMP1 plasma concentration was significantly higher in small tumors compared with T2-T3 tumors (p = 0.013). Conclusions These findings reveal an important association between tumor characteristics and expression ratios of MMP1/TIMP1 and MMP2/TIMP1 in PBLs and TIMP1 concentration in plasma. Menopausal status may influence the mRNA expression levels of MMP2 and TIMP1 as well as the MMP2/TIMP3 expression ratio in IDC of the breast.
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Tellier, Edwige, Anne Nègre-Salvayre, Beatrice Bocquet, Shigeyoshi Itohara, Yusuf A. Hannun, Robert Salvayre i Nathalie Augé. "Role for Furin in Tumor Necrosis Factor Alpha-Induced Activation of the Matrix Metalloproteinase/Sphingolipid Mitogenic Pathway". Molecular and Cellular Biology 27, nr 8 (5.02.2007): 2997–3007. http://dx.doi.org/10.1128/mcb.01485-06.
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ABSTRACT Neutral sphingomyelinase (nSMase), the initial enzyme of the sphingolipid signaling pathway, is thought to play a key role in cellular responses to tumor necrosis factor alpha (TNF-α), such as inflammation, proliferation, and apoptosis. The mechanism of TNF-α-induced nSMase activation is only partly understood. Using biochemical, molecular, and pharmacological approaches, we found that nSMase activation triggered by TNF-α is required for TNF-α-induced proliferation and in turn requires a proteolytic cascade involving furin, membrane type 1 matrix metalloproteinase (MT1-MMP), and MMP2, and leading finally to extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and DNA synthesis, in smooth muscle cells (SMC) and fibroblasts. Pharmacological and molecular inhibitors of MMPs (batimastat), furin (α1-PDX inhibitor-transfected SMC), MT1-MMP (SMC overexpressing a catalytically inactive MT1-MMP), MMP2 (fibroblasts from MMP2−/− mice), and small interfering RNA (siRNA) strategies (siRNAs targeting furin, MT1-MMP, MMP2, and nSMase) resulted in near-complete inhibition of the activation of nSMase, sphingosine kinase-1, and ERK1/2 and of subsequent DNA synthesis. Exogenous MT1-MMP activated nSMase and SMC proliferation in normal but not in MMP2−/− fibroblasts, whereas exogenous MMP2 was active on both normal and MMP2−/− fibroblasts. Altogether these findings highlight a pivotal role for furin, MT1-MMP, and MMP2 in TNF-α-induced sphingolipid signaling, and they identify this system as a possible target to inhibit SMC proliferation in vascular diseases.
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Sundrani, Deepali, Preeti Chavan-Gautam, Hemlata Pisal, Savita Mehendale i Sadhana Joshi. "Matrix metalloproteinases-2, -3 and tissue inhibitors of metalloproteinases-1, -2 in placentas from preterm pregnancies and their association with one-carbon metabolites". REPRODUCTION 145, nr 4 (kwiecień 2013): 401–10. http://dx.doi.org/10.1530/rep-12-0520.
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Maternal nutrition is an important determinant of one-carbon metabolism and defects in the one-carbon metabolism may lead to poor obstetric outcomes. This study was designed to test the hypothesis that altered intake/metabolism of micronutrients (folic acid and vitamin B12) and docosahexaenoic acid (DHA) contributes to increased homocysteine and oxidative stress leading to altered levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in women delivering preterm. We have earlier reported increased vitamin B12, homocysteine, and oxidative stress along with reduced placental DHA in women delivering preterm. In this study, we further examine the placental levels of MMP2, MMP3, TIMP1, and TIMP2 in 75 women delivering at term and 73 women delivering preterm. Placental levels of MMPs and TIMPs were determined by ELISA. Placental MMP2 and MMP3 levels were higher (P<0.01) in women delivering preterm as compared with term. There was no difference in the placental TIMP1 and TIMP2 levels in women delivering preterm and at term. Further placental MMP2 and MMP3 levels were higher (P<0.01) in women with preterm labor as compared with those in labor at term, suggesting that MMPs may favor degradation of extracellular matrix in the placenta during preterm labor. Our study for the first time suggests a crucial role of micronutrients and MMPs in preterm birth. Future studies need to examine if epigenetic modifications through the one-carbon cycle contribute to increased levels of MMPs leading to preterm deliveries.
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Zhao, Huijun, Gregory Pond, Demetrios Simos, Zhou Wang, Susan Robertson, Gurmit Singh, Lisa Vandermeer, Mark Clemons i Christina Lynn Addison. "Doxycycline-Induced Changes in Circulating MMP or TIMP2 Levels Are Not Associated with Skeletal-Related Event-Free or Overall Survival in Patients with Bone Metastases from Breast Cancer". Cancers 15, nr 3 (17.01.2023): 571. http://dx.doi.org/10.3390/cancers15030571.
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Doxycycline is often used as a promoter of inducible gene expression in preclinical models; however, it can also have direct effects on tumor growth and survival. This is due in part to its ability to inhibit cell invasion and regulate matrix metalloproteinase (MMP) expression. Given that doxycycline is also osteotropic, a clinical study to assess its effects on modulation of tumor progression or prevention of skeletal-related events (SRE) in patients with bone metastases from breast cancer (the Achilles trial) was undertaken. Patients received 100 mg of oral doxycycline twice daily for 12 weeks, with serum obtained at baseline and 4, 8 and 12 weeks post-initiation of doxycycline treatment. Exploratory analysis of the effects of doxycycline on circulating levels of MMP or tissue inhibitor of matrix metalloproteinase 2 (TIMP2) was performed in enrolled patients. Statistically significant associations were observed between MMP2, MMP9 and TIMP2 at baseline with significant associations maintained between absolute levels and changes in levels of MMP2 and TIMP2 at weeks 4–12 post initiation of doxycycline. Treatment with doxycycline generally resulted in decreases in MMP2 and MMP9 levels with concurrent upregulation of TIMP2 at 12 weeks post-initiation of doxycycline treatment. Despite this, we observed no association with the levels of any of these factors with either SRE-free or overall survival in this patient cohort. In summary, despite observing hypothesized effects of doxycycline administration on surrogate markers of its anti-tumor activity, measures of circulating levels of these biomarkers were not prognostic in this patient population.
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Murugan, Avaniyapuram Kannan, Abeer Al-Amr, Mysoon M. Al-Ansari, Pulicat S. Manogaran, Hindi Al-Hindi i Ali S. Alzahrani. "Single nucleotide polymorphisms in matrix metalloproteinase 2 (MMP2) enhance BRAFV600E mutation-mediated oncogenicity and invasiveness of papillary thyroid cancer cells". Endocrine-Related Cancer 28, nr 4 (kwiecień 2021): 273–89. http://dx.doi.org/10.1530/erc-20-0242.
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Thyroid cancer is a common endocrine neoplasm. Despite its good prognosis, it can lead to significant morbidity and mortality due to metastasis and recurrence. However, the factors involved in metastasis are not well studied. Therefore, we selected matrix metalloproteinases 2 (MMP2) and determined whether it has any role in thyroid cancer. We sequenced the exons of MMP2 in 211 samples including 16 multi-nodular goiters and 195 differentiated thyroid cancers. We identified four non-synonymous single nucleotide polymorphisms (SNPs) of the MMP2 gene in 3.06% (6/195) thyroid cancers. Of the four tumors harboring MMP2 SNPs, three (75%) concomitantly had BRAFV600E. Hence, we speculated that the MMP2 SNPs may cooperate with BRAFV600E in promoting tumor aggressiveness. Overexpression of two MMP2 SNPs (P38L and T458I) exhibited markedly enhanced gelatinase activity with an intact dimerization and induced strong cortactin foci formation in HEK293T cells. Stable expression of the two MMP2 SNPs in BRAFV600E positive BCPAP cells dramatically enhanced cell proliferation, colony formation, and focus formation. Analysis of the morphology of MMP2 SNP bearing BCPAPV600E cells exhibited highly invasive phenotypes characterized by a high rate of wound healing and enhanced cell invasion compared with parental BCPAPV600E cells bearing vector. We also determined that BCPAPV600E cells stably transfected with MMP2 SNPs were highly sensitive to the treatment of BRAF inhibitor, PLX4720. Our study demonstrates that MMP2 SNPs could cooperate with BRAFV600E to promote oncogenicity, migration, and invasiveness of PTC cells. These results suggest that a subset of papillary thyroid cancer with this genetic makeup may benefit from BRAF-mediated therapeutic interventions.
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Zhu, Xue, Mengxi Yu, Ke Wang, Wenjun Zou i Ling Zhu. "FoxM1 affects adhesive, migratory, and invasive abilities of human retinoblastoma Y-79 cells by targeting matrix metalloproteinase 2". Acta Biochimica et Biophysica Sinica 52, nr 3 (marzec 2020): 294–301. http://dx.doi.org/10.1093/abbs/gmz160.
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Abstract Forkhead box protein M1 (FoxM1) is an important transcription factor involved in various pathological processes including tumor metastasis. The changes of adhesive, migratory, and invasive abilities are considered as crucial events in tumor metastasis progression. In this study, we aimed to investigate the correlation between FoxM1 and retinoblastoma (Rb) metastasis and to explore the detailed mechanism. Wound healing, cell adhesion, and invasion assays showed that FoxM1 overexpression induced epithelial–mesenchymal transition in Y-79 cells and inhibited adhesion and subsequently promoted metastasis of Y-79 cells, while FoxM1 knockdown showed the opposite effects. A luciferase reporter assay and chromatin immunoprecipitation assay provided evidence that FoxM1 promoted matrix metalloproteinase 2 (MMP2) transcription by directly binding to and promoting MMP2 promoter. MMP2 knockdown by siRNA transfection attenuated cell metastasis of Y-79 cells induced by FoxM1 overexpression. Furthermore, the FoxM1-binding site mapped between −1167 and −1161 bp of the MMP2 promoter was identified. Our results suggested that the FoxM1–MMP2 axis plays an important role in Rb metastasis, which may be a novel target for designing therapeutic regimen to control Rb metastasis.
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Kendre, Gajanan, Rahul Raghavan, Sanith Cheriyamundath i Joseph Madassery. "Tetracycline and Glutathione Inhibit Matrix Metalloproteinase Activity: An In Vitro Study Using Culture Supernatants of L929 and Dalton Lymphoma Cell Lines". Journal of Cancer Research 2013 (29.12.2013): 1–5. http://dx.doi.org/10.1155/2013/328134.
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Tetracycline and glutathione inhibited the protease activities of matrix metalloproteinase-2 and matrix metalloproteinase-9 expressed by mouse fibrosarcoma cells (L929) and Dalton lymphoma cells, respectively. The inhibitory activity of the tetracycline may be due to its ability to chelate metal ions such as calcium and zinc. Gelatin-zymography technique was used to demonstrate the inhibitory activity of both tetracycline and glutathione. The intensity of the bands corresponding to metalloproteinase activity in zymography gel was reduced in the presence of 50–100 μg/mL of tetracycline. The presence of 10–100 μg/mL of tetracycline in the medium increased the adherence of L929 cancer cells. These results clearly indicate the antimetastatic property of tetracycline. Reduced glutathione, a compound which is produced endogenously by the cells to maintain the redox status, was shown to inhibit the matrix metalloproteinase activity (in vitro). Therefore, it is assumed that decreased glutathione levels in synovial fluids or plasma might increase the activity of MMP. Reduced glutathione at 100 μg/mL inhibited the metalloproteinase activity in gelatin-zymographic gel. As both tetracycline and glutathione exhibited an inhibitory effect on matrix metalloproteinase activity, it was of great interest to check their clinical effects on various MMP associated pathological conditions such as cancer metastasis and arthritis. Here we report that tetracycline and reduced glutathione inhibited the activity of MMP2 completely and activity of MMP9 partly.
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Liu, Gang, Fang Ren i Yongsheng Song. "Upregulation of SPOCK2 inhibits the invasion and migration of prostate cancer cells by regulating the MT1-MMP/MMP2 pathway". PeerJ 7 (12.07.2019): e7163. http://dx.doi.org/10.7717/peerj.7163.
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Background It is known that secreted protein acidic and cysteine rich (osteonectin), cwcv and kazal-like domains proteoglycan 2 (SPOCK2) plays a significant role in the development and progression of several human cancers; however, the role of SPOCK2 in prostate cancer (PCa) remains unclear. This study aimed to find the role and mechanism of SPOCK2 in the development and progression of PCa. Methods The messenger ribonucleic acid (mRNA) expression of SPOCK2 in PCa tissue was detected by real-time polymerase chain reaction (PCR). Upregulation of the SPOCK2 gene was achieved using the DU145 and LNCaP cells by transfecting the cells with SPOCK2 recombinant fragment. Cell invasion and migration ability were detected by transwell chamber and wound healing assay. The expression of membrane-type 1 matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase 2 (MMP2) in the cells was detected by Western Blot and zymography gel assay. Results The mRNA level of SPOCK2 was significantly lower in the PCa tissue compared to benign prostate hyperplasia. Upregulation of SPOCK2 inhibited cell invasion and migration in DU145 and LNCaP cells, inhibited the expression of MT1-MMP and MMP2 and, inhibited activation of MMP2 in DU145 and LNCaP cells. Conclusion SPOCK2 is associated with the progression of PCa. Upregulation of SPOCK2 can inhibit PCa cell invasion and metastasis by decreasing MT1-MMP and MMP2 gene expression and decreasing MMP2 protein activation.
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Suenaga, Mitsukuni, Marta Schirripa, Shu Cao, Wu Zhang, Dongyun Yang, Yan Ning, Francesca Bergamo i in. "Matrix metalloproteinase-related gene polymorphisms to predict efficacy of regorafenib in patients with metastatic colorectal cancer." Journal of Clinical Oncology 36, nr 4_suppl (1.02.2018): 692. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.692.
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692 Background: Matrix metalloproteinases (MMPs) are proteolytic enzyme for extracellular matrix and involved in regulation of tumor environment including angiogenesis. MMP-2 and MMP-9 were reported to be prognostic marker of anti-angiogenic therapy. We tested whether genetic polymorphisms in the MMP family predict clinical outcomes in patients with refractory mCRC receiving regorafenib. Methods: 228 patients with mCRC receiving regorafenib were included in this pooled analysis combining two different cohorts from Italy and Japan (median age, 62 years; male, 51.5%; median follow-up time, 26.2 months; Italian/Japanese, 150/79). Six single nucleotide polymorphisms (SNPs) of five genes in MMPs ( MMP2, MMP9, MMP14, TIMP2, CD44) were analyzed by PCR-based direct sequencing. Correlations between candidate SNPs and progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves and log-rank test. Disease control was compared by Fisher’s exact test. Multivariable analyses were conducted using the Cox proportional hazard regression model. Results: In univariate analysis, patients carrying the G/G variant in MMP2 rs1477017 had a significantly shorter OS compared to those with any A allele (4.4 vs. 7.8 months, HR 1.85, 95%CI: 1.13-3.03, P= 0.011). The findings were confirmed in multivariable analysis (HR 1.84, 95%CI: 1.11-3.07, P= 0.019). Although the frequency of the T/T variant in MMP9 rs2274755 was considerably low, the T/T variant was associated with shorter PFS and OS compared to any G allele in univariate analysis (1.7 vs. 2.1 months, HR 2.53, 95%CI: 1.17-5.46, P= 0.011; 3.9 vs. 7.6 months, HR 2.51, 95%CI: 1.11-5.72, P= 0.021) and multivariable analysis (HR 3.04, P= 0.009; HR 5.20, P< 0.001). No significant interaction was shown between the SNPs and cohorts. Disease control was significantly infrequent in patients carrying the T/T variant in MMP9 rs2274755 ( P= 0.046). Conclusions: Our data suggest that MMPs network potentially mediates tumor angiogenesis responding to regorafenib. The MMP2 and MMP9 SNPs may predict efficacy of regorafenib in patients with refractory mCRC. However, this preliminary finding warrants further validation.
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Shurygina, Irina, Lyubov Rodionova, Natalia Ayushinova, Elena Chepurnykh, Irina Trukhan i Michael Shurygin. "Effect of the p38 MAPK Inhibitor on the Expression of Metalloproteinases and Their Inhibitors during the Formation of Abdominal Adhesions". International Journal of Biomedicine 11, nr 4 (10.12.2021): 446–50. http://dx.doi.org/10.21103/article11(4)_oa9.
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Background: The aim of this study was to assess the effect of blockade of the p38 mitogen-activated protein kinase (MAPK) on the expression of genes encoding metalloproteinases (MMPs) during the formation of adhesions in the abdominal cavity. Methods and Results: The experiments were carried out on male Wistar rats (n=75). The studies were carried out in two groups: Group 1 (control, n=35) – modelling the adhesive process; Group 2 (experimental, n=35) – modelling the adhesive process with intraperitoneal administration of Seroguard®—a prolonged form of the p38 MAPK inhibitor. The expression of the MMP1a, MMP2, MMP7, MMP9, and TIMP genes was assessed using real-time PCR. In the control group, overexpression of the MMP1a and MMP7 genes began from 6 hours after modeling the adhesive process, MMP9 – from Day 1, MMP2 – from Day 7 and persisted until the end of observation. With local blockade of p38 MAPK, the level of overexpression of genes encoding MMPs in the early stages was higher than in the control group (MMP1a – by Day 1; MMP7 – by 6 hours and Day 1, MMP9 – by 12 hours). From Day 3 to Day 14, the MMP1a and MMP7 expression in the experimental group was significantly lower than in the control group. Conclusion: The performed study demonstrated the involvement of different types of MMPs—collagenases (MMP1a), gelatinases (MMP2 and 9), matrilysins (MMP7)—in the rearrangement of the extracellular matrix during the process of adhesion formation in the abdominal cavity.
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Fang, Lu, Xiao-Jun Du, Xiao-Ming Gao i Anthony M. Dart. "Activation of peripheral blood mononuclear cells and extracellular matrix and inflammatory gene profile in acute myocardial infarction". Clinical Science 119, nr 4 (18.05.2010): 175–83. http://dx.doi.org/10.1042/cs20100011.
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Inflammation and ECM (extracellular matrix) remodelling play important roles in LV (left ventricular) remodelling following acute MI (myocardial infarction). Previous studies show elevated plasma MMP (matrix metalloproteinase) levels in patients with acute MI, but their sources are not clear. The recruitment of mononuclear cells into the infarcted myocardium is critical for inflammatory responses, but their exact roles in LV remodelling have not been fully investigated, as it is difficult to isolate and study the function of regional inflammatory cells. To address these questions, we isolated PBMCs (peripheral blood mononuclear cells) from blood samples of patients with acute MI or stable angina, or healthy controls (n=14, 8 and 12 respectively). PBMCs were cultured for 24 h and the MMP9 level in the culture medium was measured by gelatin zymography, and MMP9 gene expression was measured by real-time PCR. Two superarrays (ECM and adhesion molecules, and common cytokines; 84 genes included in each array) were employed to screen gene expression profiles by PBMCs in five patients with acute MI and five controls. We found that MMP9 expression by PBMCs at both the mRNA and protein levels was increased 2-fold (both P<0.05) in patients with acute MI compared with the two control groups. Notably, MMP2 was not expressed by PBMCs. Superarray screening revealed that PBMCs not only expressed MMPs, TIMPs (tissue inhibitors of metalloproteinases) and matrix proteins, but also served as an important source of cell adhesion molecules, inflammatory cytokines and growth factors. A total of 42 genes were differentially expressed in patients with acute MI compared with controls. Expression of selected genes was confirmed by real-time PCR. In conclusion, PBMCs constitute a key cellular source for elevated plasma MMP9, but not for MMP2. PBMCs also contribute to systemic and regional inflammation and matrix remodelling in acute MI.
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Timokhina, Elena, Vadim Zinin, Irina Ignatko, Sapyat Ibragimova, Larisa Belotserkovtseva i Aleksander Strizhakov. "Matrix metalloproteinases MMP-2 and MMP-9 as markers for the prediction of preeclampsia in the first trimester". Česká gynekologie 86, nr 4 (30.08.2021): 228–35. http://dx.doi.org/10.48095/cccg2021228.
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Summary: Introduction: Preeclampsia is a life-threatening condition for the mother and foetus. Globally, it is diagnosed in 10 mil. women every year, which accounts for 3% to 8% of all pregnancies. Currently there is no proven effective treatment for preeclampsia. The aforesaid text actualises the issue of predicting this complication. To determine the prognostic significance of matrix metalloproteinases-2 and -9 levels as early markers of preeclampsia, the present prospective study was conducted. Materials and methods: The levels of matrix metalloproteinases-2 and -9 were assessed in 72 patients. Thirty-four of them subsequently developed preeclampsia during pregnancy (20 patients with moderate preeclampsia, 14 patients with severe preeclampsia), and constituted the basic group; 38 patients made up the control group. Results: In pregnant women with the subsequent development of preeclampsia, the level of matrix metalloproteinase-2 at 11–13 weeks of gestation was 155 ± 73.4 ng/mL and significantly exceeded its level in pregnant women without hypertensive disorders – 75.0 ± 32.8 ng/mL. The study conducted demonstrates a significantly lower concentration of matrix metalloproteinase-9 in pregnant women with preeclampsia compared to the control – 749 ± 296 ng/mL and 1,667 ± 552 ng/mL (P < 0.001). The performed research figures that in the first trimester, the cut-off value of matrix metalloproteinase-2 for predicting the development of preeclampsia is ≥ 102 ng/mL (sensitivity 88.24% and specificity 82.76%). For matrix metalloproteinase-9, a level of ≤ 980 ng/mL in the first trimester predicts the development of preeclampsia with a sensitivity of 85.29% and a specificity of 84.48%. Conclusion: The study established the cut-off values of matrix metalloproteinases-2 and -9 for predicting the development of preeclampsia in the first trimester.
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Dean, Richard A., Georgina S. Butler, Yamina Hamma-Kourbali, Jean Delbé, David R. Brigstock, José Courty i Christopher M. Overall. "Identification of Candidate Angiogenic Inhibitors Processed by Matrix Metalloproteinase 2 (MMP-2) in Cell-Based Proteomic Screens: Disruption of Vascular Endothelial Growth Factor (VEGF)/Heparin Affin Regulatory Peptide (Pleiotrophin) and VEGF/Connective Tissue Growth Factor Angiogenic Inhibitory Complexes by MMP-2 Proteolysis". Molecular and Cellular Biology 27, nr 24 (1.10.2007): 8454–65. http://dx.doi.org/10.1128/mcb.00821-07.
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ABSTRACT Matrix metalloproteinases (MMPs) exert both pro- and antiangiogenic functions by the release of cytokines or proteolytically generated angiogenic inhibitors from extracellular matrix and basement membrane remodeling. In the Mmp2 −/− mouse neovascularization is greatly reduced, but the mechanistic aspects of this remain unclear. Using isotope-coded affinity tag labeling of proteins analyzed by multidimensional liquid chromatography and tandem mass spectrometry we explored proteome differences between Mmp2 −/− cells and those rescued by MMP-2 transfection. Proteome signatures that are hallmarks of proteolysis revealed cleavage of many known MMP-2 substrates in the cellular context. Proteomic evidence of MMP-2 processing of novel substrates was found. Insulin-like growth factor binding protein 6, follistatin-like 1, and cystatin C protein cleavage by MMP-2 was biochemically confirmed, and the cleavage sites in heparin affin regulatory peptide (HARP; pleiotrophin) and connective tissue growth factor (CTGF) were sequenced by matrix-assisted laser desorption ionization-time of flight mass spectrometry. MMP-2 processing of HARP and CTGF released vascular endothelial growth factor (VEGF) from angiogenic inhibitory complexes. The cleaved HARP N-terminal domain increased HARP-induced cell proliferation, whereas the HARP C-terminal domain was antagonistic and decreased cell proliferation and migration. Hence the unmasking of cytokines, such as VEGF, by metalloproteinase processing of their binding proteins is a new mechanism in the control of cytokine activation and angiogenesis.
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Yu-Ju Wu, Caren, Chia-Hua Chen, Chun-Yen Lin, Li-Ying Feng, Yung-Chang Lin, Kuo-Chen Wei, Chiung-Yin Huang, Jia-You Fang i Pin-Yuan Chen. "CCL5 of glioma-associated microglia/macrophages regulates glioma migration and invasion via calcium-dependent matrix metalloproteinase 2". Neuro-Oncology 22, nr 2 (8.10.2019): 253–66. http://dx.doi.org/10.1093/neuonc/noz189.
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Abstract Background Glioma-associated microglia/macrophages (GAMs) comprise macrophages of peripheral origin and brain-intrinsic microglia, which support tumor progression. Chemokine C-C ligand 5 (CCL5) is an inflammatory mediator produced by immune cells and is involved in tumor growth and migration in several cancers, including glioma. However, the mechanisms detailing how CCL5 facilitates glioma invasion remain largely unresolved. Methods Glioma migration and invasion were determined by wound healing, transwell assay, and 3D µ-slide chemotaxis assay. The expression levels of CCL5, CD68, matrix metalloproteinase 2 (MMP2), phosphorylated Ca2+/calmodulin-dependent protein kinase II (p-CaMKII), p-Akt, and phosphorylated proline-rich tyrosine kinase 2 were determined by cytokine array, quantitative PCR, western blot, or immunohistochemistry. Zymography and intracellular calcium assays were used to analyze MMP2 activity and intracellular calcium levels, respectively. Results CCL5 modulated the migratory and invasive activities of human glioma cells in association with MMP2 expression. In response to CCL5, glioma cells underwent a synchronized increase in intracellular calcium levels and p-CaMKII and p-Akt expression levels. CCL5-directed glioma invasion and increases in MMP2 were suppressed after inhibition of p-CaMKII. Glioma cells tended to migrate toward GAM-conditioned media activated by granulocyte-macrophage colony-stimulating factor (GM-CSF) in which CCL5 was abundant. This homing effect was associated with MMP2 upregulation, and could be ameliorated either by controlling intracellular and extracellular calcium levels or by CCL5 antagonism. Clinical results also revealed the associations between CCL5 and GAM activation. Conclusion Our results suggest that modulation of glioma CaMKII may restrict the effect of CCL5 on glioma invasion and could be a potential therapeutic target for alleviating glioma growth.
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Mogulevtseva, J. A., A. V. Mezentsev i S. A. Bruskin. "RNAI-MEDIATED SILENCING OF MATRIX METALLOPROTEINASE 1 IN EPIDERMAL KERATINOCYTES INFLUENCES THE BIOLOGICAL EFFECTS OF INTERLEUKIN 17A". Vavilov Journal of Genetics and Breeding 22, nr 4 (3.07.2018): 425–32. http://dx.doi.org/10.18699/vj18.378.
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Matrix metalloproteinases (MMPs) are important for the pathogenesis of psoriasis and other autoimmune disorders. In the extracellular matrix, accumulation of proinflammatory cytokines, such as interleukin 17A (IL-17A), leads to induction of several MMPs, including MMP1. MMPs change the composition and other properties of the extracellular matrix. These changes facilitate tissue remodeling and promote the development of psoriatic plaques. The aim of this study was to explore how MMP1 silencing might influence the biological effects of IL-17A on migration and proliferation of human epidermal keratinocytes and the expression of genes involved in their division and differentiation. The experiments were performed with MMP1-deficient and control epidermal keratinocytes, HaCaT-MMP1 and HaCaT-KTR, respectively. Cell proliferation and migration were assessed by comparative analysis of the growth curves and scratch assay, respectively. To quantify cell migration, representative areas of cell cultures were photographed at the indicated time points and compared to each other. Changes in gene expression were analyzed by real-time PCR. The obtained results demonstrated that MMP1 silencing in the cells treated with IL-17A resulted in downregulation of MMP9 and -12, FOSL1, CCNA2, IVL, KRT14 and -17 as well as upregulation of MMP2, CCND1 and LOR. Moreover, MMP1 silencing led to a decrease in cell proliferation and an impairment of cell migration. Thus, MMP1-deficiency in epidermal keratinocytes can be beneficial for psoriasis patients that experience an accumulation of IL-17 in lesional skin. Knocking MMP1 down could influence migration and proliferation of epidermal keratinocytes in vivo, as well as help to control the expression of MMP1, -2, -9 и -12, CCNA2, CCND1, KRT14 and -17 that are crucial for the pathogenesis of psoriasis.
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Yu, Lin, Chun-Yu Wang, Jiandang Shi, Lin Miao, Xiaoling Du, Doris Mayer i Ju Zhang. "Estrogens Promote Invasion of Prostate Cancer Cells in a Paracrine Manner through Up-Regulation of Matrix Metalloproteinase 2 in Prostatic Stromal Cells". Endocrinology 152, nr 3 (1.03.2011): 773–81. http://dx.doi.org/10.1210/en.2010-1239.
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Accumulating evidence suggests an enhancing effect of estrogens on prostate cancer (PCa) progression. Matrix metalloproteinase 2 (MMP2), which plays an important role in prostate cancer invasion, is mainly expressed in prostatic stromal cells (PrSC). Here we show that estradiol (E2) treatment up-regulates MMP2 production in PrSC, which promotes PCa cell invasion in a paracrine manner. Conditioned medium (CM) was collected from E2-treated prostatic stromal cell line WPMY-1 and primary PrSC. The CM of E2-treated WPMY-1 and PrSC promoted invasion of PCa cells, as measured by Matrigel transwell assays. Treatment with E2 and 1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole, an estrogen receptor-alpha (ERα) specific agonist, significantly up-regulated MMP2 expression in WPMY-1 and PrSC cells at both mRNA and protein levels. The CM treated with an anti-MMP2 antibody lost the stimulatory effect on invasion of PCa cells. The ER inhibitor ICI 182,780, as well as a TGFβ1 neutralizing antibody and ERα-specific small interfering RNA effectively suppressed E2-induced MMP2 expression in WPMY-1 cells. Mechanistic studies showed that E2 up-regulated MMP2 in an indirect manner: E2 induced TGFβ1 expression via ERα; TGFβ1 stimulated MMP2 expression in PrSC; the invasion of PCa cells were stimulated by elevated MMP2 expression induced by E2 in a paracrine manner. Our data show that E2 induces MMP2 expression in WPMY-1 and PrSC cells, which was mediated by TGFβ1. The effect of E2 on invasion of PCa cells is mediated by up-regulation of MMP2 in a paracrine mechanism.
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Qin, Li, Lan Liao, Aisling Redmond, Leonie Young, Yuhui Yuan, Hongwu Chen, Bert W. O'Malley i Jianming Xu. "The AIB1 Oncogene Promotes Breast Cancer Metastasis by Activation of PEA3-Mediated Matrix Metalloproteinase 2 (MMP2) and MMP9 Expression". Molecular and Cellular Biology 28, nr 19 (21.07.2008): 5937–50. http://dx.doi.org/10.1128/mcb.00579-08.
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ABSTRACT Amplified-in-breast cancer 1 (AIB1) is an overexpressed transcriptional coactivator in breast cancer. Although overproduced AIB1 is oncogenic, its role and underlying mechanisms in metastasis remain unclear. Here, mammary tumorigenesis and lung metastasis were investigated in wild-type (WT) and AIB1−/− mice harboring the mouse mammary tumor virus-polyomavirus middle T (PyMT) transgene. All WT/PyMT mice developed massive lung metastasis, but AIB1−/−/PyMT mice with comparable mammary tumors had significantly less lung metastasis. The recipient mice with transplanted AIB1−/−/PyMT tumors also had much less lung metastasis than the recipient mice with transplanted WT/PyMT tumors. WT/PyMT tumor cells expressed mesenchymal markers such as vimentin and N-cadherin, migrated and invaded rapidly, and formed disorganized cellular masses in three-dimensional cultures. In contrast, AIB1−/−/PyMT tumor cells maintained epithelial markers such as E-cadherin and ZO-1, migrated and invaded slowly, and still formed polarized acinar structures in three-dimensional cultures. Molecular analyses revealed that AIB1 served as a PEA3 coactivator and formed complexes with PEA3 on matrix metalloproteinase 2 (MMP2) and MMP9 promoters to enhance their expression in both mouse and human breast cancer cells. In 560 human breast tumors, AIB1 expression was found to be positively associated with PEA3, MMP2, and MMP9. These findings suggest a new alternative strategy for controlling the deleterious roles of these MMPs in breast cancer by inhibiting their upstream coregulator AIB1.
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Yuan, Yuan, Hisao Naito, Kazuya Kitamori, Sayuki Hashimoto, Tomomi Asano i Tamie Nakajima. "The antihypertensive agent hydralazine reduced extracellular matrix synthesis and liver fibrosis in nonalcoholic steatohepatitis exacerbated by hypertension". PLOS ONE 15, nr 12 (14.12.2020): e0243846. http://dx.doi.org/10.1371/journal.pone.0243846.
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Hypertension is an important risk factor for nonalcoholic steatohepatitis. We have previously demonstrated that hypertensive rats fed a high fat and cholesterol (HFC) diet incurred a more severe hepatic inflammatory response and fibrosis. Here we investigated the role of hypertension in NASH by comparing HFC-induced hepatic fibrogenesis between spontaneously hypertensive rats (SHRs) and their normotensive Wistar Kyoto counterpart. Compared to the counterpart, the HFC diet led to stronger aggregation of CD68-positive macrophages in SHRs. HFC feeding also resulted in significantly higher upregulation of the fibrosis-related gene alpha-smooth muscle actin in SHR. The HFC diet induced higher overexpression of serum tissue inhibitor of metalloproteinase-1 (TIMP1) and greater suppression of matrix metalloproteinase-2 (MMP2):TIMP1, MMP8:TIMP1, and MMP9:TIMP1 ratios, as a proxy of the activities of these MMPs in SHR. Administration of the antihypertensive agent hydralazine to SHRs significantly ameliorated HFC-induced liver fibrosis; it suppressed the aggregation of CD68-positive macrophages and the upregulation of platelet-derived growth factor receptor beta, and collagen, type 1, alpha-1 chain. In conclusion, a hypertensive environment exacerbated the hepatic fibrogenetic effects of the HFC diet; while the effects were partially reversed by the antihypertensive agent hydralazine. Our data suggest that antihypertensive drugs hold promise for treating NASH exacerbated by hypertension.
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Казеко, Л. А., В. А. Захарова i Ю. Д. Бенеш. "The Role of Matrix Metalloproteinases and Their Tissue Inhibitors in the Pathogenesis of Aggressive Periodontitis". Стоматология. Эстетика. Инновации, nr 4 (25.11.2022): 329–36. http://dx.doi.org/10.34883/pi.2022.6.4.006.
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Нарушение баланса между уровнями MMPs и TIMPs является одним из звеньев патогенеза патологии периодонта. Данные о том, какие именно MMPs играют решающую роль в определении характера течения периодонтитов, весьма противоречивы. Цель. Установить роль параметров стромальной экспрессии MMPs и TIMPs в биопсийном материале десен пациентов в патогенезе быстропрогрессирующего периодонтита. Материалы и методы. Исследован биопсийный материал десен 26 пациентов с быстропрогрессирующим характером течения периодонтита, окрашенный с использованием моноклональных антител к MMP (-1, -2, -8, -9, -13, -14) и TIMP (-1, -2). Морфометрический и статистический анализ выполнен с использованием AperioImageScopev12.4.0.5043, Statistica10.0, р<0,01. Результаты. В группе пациентов с быстропрогрессирующим периодонтитом имеют место сопоставимые или более низкие параметры позитивности экспрессии MMP8 (5%), MMP9 (0,6%) и ММР13 (10%) по сравнению с таковыми ТIMP1 (12,5%) и TIMP2 (42%). Высокие же параметры позитивности экспрессии ММР1 (78,5%), ММР2 (56,5%) и ММР14 (77,0%), которые в 4–9 раз превышали таковые TIMP1 и до 6 раз TIMP2, отражают низкую эффективность ингибирующего действия на них вышеназванных TIMPs и, вероятно, вносят основной вклад в агрессивное течение периодонтита. Заключение. Сравнительный анализ уровней экспрессии MMPs и TIMPs показал, что в группе пациентов с быстропрогрессирующим течением периодонтита в ответ на рост параметров экспрессии MMPs значимо повышается экспрессия как TIMP1, так и TIMP2 с более эффективным ингибированием ими MMP8, MMP9 и ММР13. Сохранение же значимо более высоких параметров экспрессии ММР1, ММР2 и ММР14 по сравнению с таковыми TIMP1 и TIMP2 является отражением дисбаланса их экспрессии и, вероятно, может иметь решающее значение в патогенезе быстропрогрессирующей деструкции периодонтальных тканей и утраты альвеолярной кости. The imbalance between MMPs and TIMPs levels is one of the links in the pathogenesis of periodontal pathology. The data on which MMPs play a crucial role in determining the type of periodontitis course are quite controversial. Purpose. To determine the parameters of stromal expression of MMPs and TIMPs in the gingival biopsy material of patients with aggressive periodontitis. Material and methods. The gingival biopsy from 26 patients with aggressive periodontitis (AgP, n=26) was analyzed. Morphometric and statistical analysis of MMPs (-1, -2, -8, -9, -13, -14) and TIMP1 expression was performed using AperioImageScope v12.4.0.5043, Statistica 10.0, p<0.05. Results. In the AgP group, there are comparable or lower parameters of positive expression of MMP8 (5%), MMP9 (0.6%) and MMP13 (10%) compared with those of TIMP1 (12.5%) and TIMP2 (42%). The high parameters of the positive expression of MMP1 (78.5%), MMP2 (56.5%) and MMP14 (77.0%), which were 4–9 times higher than those of TIMP1 and up to 6 times TIMP2, reflect the low effectiveness of the inhibitory effect of the above-mentioned TIMPs on them and probably make the main contribution to the aggressive course of periodontitis. Conclusion. Comparative analysis of MMPs and TIMPs expression levels showed that in the AgP group, in response to an increase in MMPs expression parameters, the expression of both TIMP1 and TIMP2 significantly increased with more effective inhibition of MMP8, MMP9 and MMP13. The preservation of significantly higher expression parameters of MMP1, MMP2 and MMP14 compared to those of TIMP1 and TIMP2 is a reflection of the imbalance of their expression and, probably, may be crucial in the pathogenesis of progressive destruction of periodontal tissues and loss of alveolar bone.