Matrix Metalloproteinase System Research Articles

Features of The Dynamics of Profibrotic Markers and Regression of Left Ventricular Hypertrophy After Renal Denervation in Patients With Resistant Hypertension and Stenosing Atherosclerosis of the Coronary Arteries.

To compare the changes in serum concentrations of matrix metalloproteinases (MMPs) and their tissue inhibitor (TIMP) to the dynamics of blood pressure (BP) and parameters of left ventricular hypertrophy (LVH) 6 months after renal denervation (RD) in patients with resistant arterial hypertension (RAH) and complicated coronary atherosclerosis. In 22 RAH patients with complicated coronary atherosclerosis (revascularization and/or history of myocardial infarction (MI)), 24-hour BP monitoring, echocardiography, and measurement of blood MMPs and TIMP were performed at baseline and six months after RD. The comparison group consisted of 48 RAH patients without a history of coronary revascularization or MI. In 6 months after RD, BP was decreased comparably in both groups. In the group of complicated atherosclerosis, there were no significant changes in profibrotic markers or LVH parameters. Thus, at baseline and after 6 months, the values of the studied indicators were the following: left ventricular myocardial mass (LVMM) 233.1±48.1 and 243.0±52.0 g, LVMM index 60.6±14.5 and 62.8±10 .9 g/m2.7, proMMP-1 4.9 [2.1; 7.7] and 3.6 [2.0; 9.4] ng/ml, MMP-2 290.4 [233.1; 352.5] and 352.2 [277.4; 402.9] ng/ml, MMP-9 220.6 [126.9; 476.7] and 263.5 [82.9; 726.2] ng/ml, TIMP-1 395.7 [124.7; 591.4] and 424.2 [118.2; 572.0] ng/ml, respectively. In the comparison group, on the contrary, there was a significant decrease in LVMM from 273.6±83.3 g to 254.1±70.4 g, LVMM index from 67.1±12.3 to 64.0±14.4 g/m2.7, proMMP-1 from 7.2 [3.6; 11.7] to 5.9 [3.5; 10.9] ng/ml, MMP-2 from 328.9 [257.1; 378.1] to 272.8 [230.2; 343.2] ng/ml, MMP-9 from 277.9 [137.0; 524.0] to 85.5 [34.2; 225.9] ng/ml, and the MMP-9/TIMP-1 ratio from 0.80 [0.31; 1.30] to 0.24 [0.07; 0.76]. The BP dynamics in this group was inversely correlated with MMP-2 at 6 months (r=-0.38), and the MMP-9/TIMP-1 ratio was correlated with LVMM and the LVMM index at baseline (r=0.39 and r=0.39) and at 6 months (r=0.37 and r=0.32). The change in TIMP-1 from 543.9 [277.5; 674.1] to 469.8 [289.7; 643.6] ng/ml was not significant (p=0.060). In RAH patients with complicated coronary atherosclerosis, the dynamics of profibrotic biomarkers and LVH parameters after RD was absent despite the pronounced antihypertensive effect, probably due to the low reversibility of cardiovascular remodeling processes or more complex regulatory mechanisms of the MMP system.

Matrix metalloproteinases and morphological features in chronic liver diseases

Aim of investigation. To study the relationship of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) with a morphological features of chronic liver diseases (CLD). Materials and methods. 76 patients with CLD of viral or alcoholic etiology aged from 18 to 64 years were examined. Chronic hepatitis was diagnosed in 59 patients, liver cirrhosis (class A according Child-Pugh score) was detected in 17 cases. The control group consisted of 72 practically healthy people. The blood levels of MMP-1, MMP-9, TIMP-1 were determined by enzyme immunoassay, and the ratio of TIMP-1/MMP-1, TIMP-1/MMP-9 was calculated. Results. There was an increase in the concentration of TIMP-1 and MMP-1 in the blood, the ratio of TIMP-1/MMP-9, a decrease in the ratio of TIMP-1/MMP-1 in CLD. In moderate and severe histological activity of CLD the levels of TIMP-1 and MMP-9 were higher, and the ratio of TIMP-1/MMP-9 was lower than in patients with histological activity index values less than 9 points. In patients with liver cirrhosis (fibrosis F4), the maximum values of TIMP-1, TIMP-1/MMP-1 and TIMP-1/MMP-9 were determined, which differed from the corresponding values for fibrosis F0-1 and F2. The blood levels of MMP-9 more than 410 ng/ml predicted severe inflammation in CLD with an accuracy of 82.9 %. The blood levels of TIMP-1 above 624 ng/ml, TIMP-1/MMP-1 more than 37.1, TIMP-1/MMP-9 more than 7.33 had high accuracy (82.9, 80.3, 80.3 %, respectively) in the prediction of liver cirrhosis (fibrosis F4). Conclusion. The imbalance in the matrix metalloproteinase system is associated with the morphological features of CLD and is characterized by hyperexpression of MMP-9 in cases of severe inflammation and increased activity of TIMP-1 in severe stages of liver fibrosis.

Matrix metalloproteinases system profile analysis and their endogenous inhibitors in children with periodontal diseases and various dysplasia phenotypes

Relevance. The search and development of modern non-invasive methods for early periodontal disease detection are of scientific and practical value for a personalized approach to disease course prognosis and explaining the choice of treatment tactics. Morphological immaturity, high intensity of anabolic processes, functional failure of neurohumoral, endocrine and immunological defence systems combined with an imbalance between the synthesis and degradation of extracellular matrix components in children with undifferentiated connective tissue disease (UCTD) significantly increases the risk of developing periodontal diseases. The available data on the activity of salivary matrix metalloproteinases (MMPs), which play a leading role in regulating connective tissue protein metabolism and bone remodelling mechanisms in children with UCTD of various degrees, are scarce and require further study.Purpose. The study aimed to explain the clinical, diagnostic and prognostic value of MMPs as markers of inflammatory periodontal diseases in children with UC TD and dysplastic disorders of various se verity.Material and methods. The study included 67 children with UCTD (main group) and 34 children of health groups I and II (comparison group) aged 12-17. The UCTD severity was established according to the diagnostic criteria by L. N. Abbakumova (2006) and a scale for assessing the significance of phenotypic and visceral signs. The main group was divided into two subgroups: Subgroup 1 (n = 38) – children with mild and moderate UCTD; Subgroup 2 (n=29) – children with severe UCTD. The studied groups had their periodontal status assessed, as well as the concentration of MMP-1, MMP-2, MMP-8, MMP-9 and their tissue inhibitors (TIMP-1, TIMP-2) in the oral fluid identified using the enzyme immunoassay, along with calculation done for the MMP ⁄ TIMP coefficients that set a balance between the degradation and synthesis of collagen.Results. The children with phenotypic signs of UCTD in the oral fluid appeared to show a statistically significant increase in the MMP-1, MMP-2, MMP-8, and MMP-9 levels and an imbalanced ratio in MMP-1⁄TIMP-1, MMP- 2⁄TIMP-2, MMP-8⁄TIMP-1, MMP-9⁄TIMP-1, compared with health groups I, II. An increase in the MMP-1, MMP-2, and MMP-8 concentrations, along with dominating expression of MMP-9 over TIMP-1 in the oral fluid of children of Subgroup 2, causes an increase in intensity and prevalence of periodontal diseases compared to the patients in Sub-group 1 and comparison group.Conclusion. Thus, when children with UCTD don’t demonstrate an increase in specific tissue inhibitors TIMP-1 and TIMP-2 in their oral fluid, along with an increase in the levels of the respective matrixins is the key pathogenetic factor in the degradation of extracellular matrix proteins, which causes a depressing impact on the proliferative activity in the periodontal set of tissues.

Serum TGF-β1 and CD14 Predicts Response to Anti-TNF-α Therapy in IBD.

Tumor necrosis factor-alpha (TNF-α) agonists revolutionized therapeutic algorithms in inflammatory bowel disease (IBD) management. However, approximately every third IBD patient does not respond to this therapy in the long term, which delays efficient control of the intestinal inflammation. We analyzed the power of serum biomarkers to predict the failure of anti-TNF-α. We collected serum of 38 IBD patients at therapy prescription and 38 weeks later and analyzed them with relation to therapy response (no-, partial-, and full response). We used enzyme-linked immunosorbent assay to quantify 16 biomarkers related to gut barrier (intestinal fatty acid-binding protein, liver fatty acid-binding protein, trefoil factor 3, and interleukin (IL)-33), microbial translocation, immune system regulation (TNF-α, CD14, lipopolysaccharide-binding protein, mannan-binding lectin, IL-18, transforming growth factor-β1 (TGF-β1), osteoprotegerin (OPG), insulin-like growth factor 2 (IGF-2), endocrine-gland-derived vascular endothelial growth factor), and matrix metalloproteinase system (MMP-9, MMP-14, and tissue inhibitors of metalloproteinase-1). We found that future full-responders have different biomarker profiles than non-responders, while partial-responders cannot be distinguished from either group. When future non-responders were compared to responders, their baseline contained significantly more TGF-β1, less CD14, and increased level of MMP-9, and concentration of these factors could predict non-responders with high accuracy (AUC = 0.938). Interestingly, during the 38 weeks, levels of MMP-9 decreased in all patients, irrespective of the outcome, while OPG, IGF-2, and TGF-β1 were higher in non-responders compared to full-responders both at the beginning and the end of the treatment. The TGF-β1 and CD14 can distinguish non-responders from responders. The changes in biomarker dynamics during the therapy suggest that growth factors (such as OPG, IGF-2, and TGF-β) are not markedly influenced by the treatment and that anti-TNF-α therapy decreases MMP-9 without influencing the treatment outcome.

Involvement of matrix metalloproteinase 1 and urokinase-type plasminogen activator in the PKCα-p38 MAPK pathway-mediated progression of human liver cancer cells.

Our previous studies have shown that the plasminogen activator (PA) and matrix metalloproteinases (MMPs) proteinase systems were highly expressed in highly malignant liver cancer cells and regulated by PKCα. This study investigates whether the PKCα regulation of PA and MMPs systems is conducted through p38 mitogen-activated protein kinase (MAPK) signaling and the pathway is responsible for promoting cell progression. We found that the expressions of p38 MAPK in both highly malignant HA22T/VGH and SK-Hep-1 liver cancer cells were higher than that in other lower malignancy liver cancer cells. Since PKCα activates p38 MAPK in progression of liver cancer, we suspected the PKCα/p38 MAPK signaling pathway to be involved in the regulation of MMPs and PA systems. When SK-Hep-1 cells were treated with SB203580 or DN-p38, only MMP-1 and u-PA mRNA expressions decreased. The p38 MAPK inhibition also decreased the cell migration and invasion. In addition, the mRNA decay assays showed that the higher expressions of MMP-1 and u-PA mRNA in SK-Hep-1 cells were due to the alteration of mRNA stability by p38 MAPK inhibition. Zymography of SK-Hep-1 cells treated with siPKCα vector also showed the decrease of the activity of MMP-1 and u-PA and confirmed changes in mRNA level. Furthermore, only the transfection of MKK6 to the siPKCα-treated SK-Hep-1 stable clone cell restored the attenuation of MMP-1 and u-PA expressions. The treatment of SK-Hep-1 cells with either inhibitor of MMP-1 or u-PA reduced migration, and the reduction was enhanced with both inhibitors. In addition, tumorigenesis was also reduced with both inhibitors. These data suggest a novel finding that MMP-1 and u-PA are critical components in PKCα/MKK6/p38 MAPK signaling pathway which mediates liver cancer cell progression, and that the targeting of both genes may be a viable approach in liver cancer treatment.

Система матриксных металлопротеиназ при хронической патологии печени

Система матриксных металлопротеиназ при хронической патологии печени

Effect of spironolactone therapy on the activity of the matrix metalloproteinase system in patients with heart failure after COVID-19

Aim. To assess the change in the activity of the matrix metalloproteinase (MMP) system after 6-month spironolactone therapy in patients with heart failure (HF) with preserved (HFpEF) and mildly reduced ejection fraction (HFmrEF) after coronavirus disease 2019 (COVID-19).Material and methods. The study included 90 patients treated at the University Clinical Hospital № 4 of the I.M. Sechenov First Moscow State Medical University with a laboratory-confirmed COVID-19. There were following inclusion criteria: age of 18-85 years; the presence of HFpEF and HFmrEF. The patients were randomized into two groups: group I (n=60) — patients with 6-month spironolactone therapy (25 mg/day) in addition to the standard therapy for HF, spironolactone was taken at a dose of 25 mg/day; Group II (comparison group, n=30) — patients who received standard therapy without spironolactone. All patients were determined plasma MMP concentrations.Results. There were no significant differences in the levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) between the groups when included in the study. A repeated investigation revealed a significant decrease in the concentrations of MMP-9 and TIMP-1 only in group I. In patients of group II, there were no significant changes in the plasma concentrations of MMP-9 and TIMP-1. The MMP-9/TIMP-1 ratio during the initial examination of patients did not have significant differences. After 6-months therapy, a significant decrease in the ratio of MMP-9/TIMP-1 was observed only in patients taking spironolactone.Conclusion. The results obtained confirm a significant decrease in MMP system activity after 6-month spironolactone therapy in patients with HFpEF and HFmrEF after COVID-19. The described antifibrotic effects of spironolactone make it possible to recommend the use of this drug in this category of patients to reduce the negative effect of MMPs on cardiovascular system.

Analysis of the Frequency Distribution and Immunohistochemical Features of the Expression of Matrix Metalloproteinases of the Second Type (MMP-2) in Preparations of Placental Tissue in Women with Recurrent Miscarriage

Формирование плаценты является инвазивным процессом и неотъемлемо связано с преобразованием базальной мембраны и экстрацеллюлярного матрикса, в котором принимает участие целый ряд ферментов, в том числе система матриксных металлопротеиназ.Цель. Изучить распределение частот генотипов генов матриксной металлопротеиназы второго типа и иммуногистохимические особенности их экспрессии в плацентарной ткани у женщин с ранними репродуктивными потерями и привычным невынашиванием беременности в анамнезе.Материалы и методы. В исследуемую группу включены 26 пациенток с привычным невынашиванием беременности и ранними репродуктивными потерями в анамнезе и 23 женщины с 3 и более физиологическими родами. В работе использованы современные молекулярно-биологические, иммуногистохимические и морфометрические методы исследования.Результаты. Данные анализа распределения частот металлопротеиназ второго типа и иммуногистохимические особенности экспрессии их в плацентарной ткани выявили различия между группами женщин с привычным невынашиванием беременности и физиологически протекающей беременностью.Выводы. Анализ генотипов системы матриксных металлопротеиназ может использоваться в клинической практике для оценки имплантационного процесса во время беременности, нарушение которого зачастую является основной причиной невынашивания на ранних сроках гестации. The formation of the placenta is an invasive process and is inherently associated with the transformation of the basement membrane and the extracellular matrix. A number of enzymes take part in this process including the system of matrix metalloproteinases.The objective of this study was to study the frequency of genotypes of matrix metalloproteinase type 2 genes and immunohistochemical features of their expression in placental tissue in women with early reproductive losses and a history of recurrent miscarriage.Materials and methods. The study group included 26 patients with recurrent miscarriage with a history of early reproductive losses and 23 women with three or more physiological deliveries. The work uses modern molecular biological, immunohistochemical and morphometric research methods.Results. Data from the analysis of the frequency distribution of metalloproteinases of the second type and the immunohistochemical features of their expression in the placental tissue revealed differences between groups of women with recurrent miscarriage and physiological pregnancy.Conclusions. Analysis of the genotypes of the matrix metalloproteinase system can be used in clinical practice to assess the implantation process during pregnancy the violation of which is often the main cause of miscarriage in the early stages of gestation.

Molecules related to diabetic retinopathy in the vitreous and involved pathways.

Diabetic retinopathy (DR) is one of the most common complications of diabetes and major cause of blindness among people over 50 years old. Current studies showed that the vascular endothelial growth factor (VEGF) played a central role in the pathogenesis of DR, and application of anti-VEGF has been widely acknowledged in treatment of DR targeting retinal neovascularization. However, anti-VEGF therapy has several limitations such as drug resistance. It is essential to develop new drugs for future clinical practice. The vitreous takes up 80% of the whole globe volume and is in direct contact with the retina, making it possible to explore the pathogenesis of DR by studying related factors in the vitreous. This article reviewed recent studies on DR-related factors in the vitreous, elaborating the VEGF upstream hypoxia-inducible factor (HIF) pathway and downstream pathways phosphatidylinositol diphosphate (PIP2), phosphoinositide-3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) pathways. Moreover, factors other than VEGF contributing to the pathogenesis of DR in the vitreous were also summarized, which included factors in four major systems, kallikrein-kinin system such as bradykinin, plasma kallikrein, and coagulation factor XII, oxidative stress system such as lipid peroxide, and superoxide dismutase, inflammation-related factors such as interleukin-1β/6/13/37, and interferon-γ, matrix metalloproteinase (MMP) system such as MMP-9/14. Additionally, we also introduced other DR-related factors such as adiponectin, certain specific amino acids, non-coding RNA and renin (pro) receptor in separate studies.

Altered gene expression of selected matrix metalloproteinase system proteins in the broiler chicken gastrointestinal tract during post-hatch development and coccidia infection

Matrix metalloproteinases (MMPs) are a family of proteases, that can process extracellular matrix (ECM) components and non-ECM molecules. MMPs can also function intracellularly in proteolytic and nonproteolytic functions. The participation of MMPs in the remodeling of the chicken gastrointestinal tract is largely unknown. The aim of the present study was to examine 1) the early neonatal developmental changes and effect of delayed access to feed immediately post-hatch (PH) and 2) the effect of Eimeria infection on mRNA expression of selected MMPs, their tissue inhibitors (TIMPs), and a disintegrin and metalloproteinase (ADAM) metallopeptidase with thrombospondin type 1 motif 8 (ADAMTS8) in the gastrointestinal tract of chicken. Protein localization of MMPs and TIMPs was also carried out in the normal ileal wall at −48, 24, and 336 h relative to hatch using immunofluorescence. In experiment 1, newly hatched Ross 708 chicks received feed and water immediately PH or were subjected to 48 h delayed access to feed. Chickens were sampled at −48, 0, 4, 24, 48, 72, 96, 144, 192, 240, 288, and 336 h PH. Ileum was collected for investigation of gene expression or fixed in paraformaldehyde for immunofluorescence. In experiments 2 and 3, Ross 708 male broilers were infected, at 21 d of age with Eimeria maxima or E. acervulina or sham-infected with water. Intestinal tissues were collected at 7 and 10 d postinfection for gene expression analysis. In general, mRNA expression patterns of all examined genes showed downregulation during the first 2 wk PH and were not affected by delay in feed access. These development-dependent changes in expression and tissue-dependent localization in the ileum of selected MMPs and TIMPs indicate that these molecules participate in the remodeling of chicken intestinal tissues during PH development. Increased expression of MMP-7 and MMP-9 transcripts in the intestine of Eimeria infected birds suggests an important role for these enzymes in the process of tissue remodeling and destruction in pathological conditions. The findings of this study are important for understanding the relationship between the expression of the MMP system and intestinal development, as well its role in gastrointestinal infection and subsequent recovery.

The importance of matrix metalloproteinases in the development of atrial fibrillation in obesity

One of the trends in modern cardiology is the study of the matrix metalloproteinase (MMP) system. Currently, an increase in plasma concentrations of some MMPs and their tissue inhibitors is considered as one of the earliest biochemical markers of myocardial fibrosis in various diseases of the cardiovascular system. Discusses the importance of MMP in the development of atrial fibrillation (AF). To study the effect of the MMP system on the development of AF in obese patients. The study included 105 patients with a body mass index of more than 30 kg/m2. Depending on the presence of AF, the patients were divided into 2 groups. The criterion for inclusion of patients in group 1 was the presence of documented AF paroxysm in 55 obese patients. The comparison group (group 2) consisted of 50 obese patients without heart rhythm disorders. When patients were included in the study, in order to assess the severity of visceral obesity, all patients underwent a general clinical examination, echocardiography. To determine the activity of the MMP system, venous blood was taken from patients. Significantly higher values of MMP-9 were detected in patients with obesity and paroxysmal AF 315.753.4 ng/ml than in patients with obesity without heart rhythm disorders 220.954.7 ng/ml (p=0.002); the values of tissue inhibitor of metalloproteinase 1 were 185.342.2 and 119.242.6 ng/ml, respectively (p=0.007). In patients with obesity and paroxysmal AF, a correlation of moderate strength between the level of MMP-9 and the volume of left atrium and a direct dependence of moderate strength between the ratio of waist volume to height and the plasma values of MMP-9 was revealed. The MMP-9 index (AUC 0.92) had a high diagnostic value for determining the probability of having a paroxysmal form of AF in obese patients. With an increase in the level of MMP-9 more than 295 ng/ml, it is possible to predict the presence of paroxysmal AF in obese patients with a sensitivity of 74.5% and a specificity of 94%. In patients with obesity and paroxysmal AF, a significant increase in the parameters of the MMP system (MMP-9 and tissue inhibitor of metalloproteinase 1) was revealed when compared with obese patients without heart rhythm disorders (p0.05). With an increase in MMP-9 of more than 285 ng/ml in obese patients, the appearance of AF with a sensitivity of 74.5% and a specificity of 94% can be predicted.

CUL5-Mediated Visfatin (NAMPT) Degradation Blocks Endothelial Proliferation and Angiogenesis via the MAPK/PI3K-AKT Signaling.

Endothelial dysfunction participates in the pathogenesis of various cardiovascular disorders, and dysregulated angiogenesis involves the vascular endothelial growth factor (VEGF)-matrix metalloproteinases (MMP) system. Nicotinamide phosphoribosyltransferase (NAMPT) is known to enhance endothelial function and angiogenesis. The study found that NAMPT overexpression protected human coronary artery endothelial cells (HCAECs) from H2O2-induced injury through promoting cell viability, inhibiting cell apoptosis, enhancing cell motility, and promoting tube formation. Through analyses based on 2 Protein-Protein Interaction databases, Mentha and BioGrid, we identified CUL5 as a protein that may interact with NAMPT, which was then validated by Co-IP experiments. Through interacting with NAMPT, CUL5 inhibited NAMPT expression. In contrast to NAMPT, CUL5 overexpression further aggravated H2O2-induced HCAEC dysfunction. In the meantime, CUL5 overexpression reduced, whereas NAMPT overexpression increased the phosphorylation of p38 and Akt and the protein levels of VEGF and MMP2. More importantly, NAMPT overexpression partially reversed the effects of CUL5 overexpression on H2O2-stimulated HCAECs and the MAPK/phosphatidylinositol 3-kinase-Akt/VEGF/MMP signaling. In conclusion, CUL5 interacts with NAMPT in H2O2-stimulated HCAECs, suppressing cell viability, promoting cell apoptosis, and inhibiting cell mobility and tube formation. NAMPT overexpression protects against H2O2-induced HCAEC dysfunction by promoting cell viability, inhibiting cell apoptosis, and enhancing cell mobility and tube formation.

Response of the matrix metalloproteinase system of the chicken ovary to prolactin treatment

The expression and activity of several matrix metalloproteinases (MMPs) has been demonstrated in the chicken ovary during various physiological states; these data indicate that MMPs are involved in the remodeling of the extracellular matrix (ECM) during follicle development, ovulation, atresia, and regression. The regulation of MMPs in the avian ovary, however, remains largely unknown. The present study aimed to examine the effect of recombinant chicken prolactin (chPRL) treatment on the expression of selected MMPs and their tissue inhibitors (TIMPs), as well as MMP-2 and MMP-9 activity in the hen ovary. Real-time polymerase chain reaction revealed changes in the mRNA expression of MMP-2, MMP-7, MMP-9, MMP-10, MMP-13, TIMP-2, and TIMP-3 in the following ovarian follicles: white, yellowish, small yellow, and the largest yellow preovulatory (F3-F1). Western blot analysis showed alterations in the abundance of latent and active forms of the MMP-2 protein, as well as the abundance of the MMP-9 protein. Moreover, minor changes in MMP-2 and MMP-9 total activities were found in ovarian follicles of chPRL-treated hens. The response to chPRL treatment depended upon the stage of follicle development, the layer of follicular wall, and the type of MMPs or TIMPs studied. In general, the results indicate that chPRL, is a positive regulator of MMP expression in the yellow preovulatory follicles. Our findings suggest that PRL participates in the mechanisms orchestrating ECM turnover during ovarian follicular development in the hen ovary via regulating the transcription, translation, and/or activity of some constituents of the MMP system.

Enhanced transforming growth factor-beta signaling and fibrosis in the pectoralis major muscle of broiler chickens affected by wooden breast myopathy

Fibrosis has also been recorded as a prominent pathological feature within wooden breast (WB) myopathy of broiler chickens. This study was conducted to evaluate the accumulation of fibril collagen, deposition of the extracellular matrix (ECM) components, and the underlying mechanism mediating the pathogenic fibrotic process in the pectoralis major (PM) muscle of WB-affected birds. Broiler chickens were categorized into the control and WB groups based on the evaluation of myopathic lesions. Results indicated that the total content and area of collagen in cross-sections of the PM muscle, as well as the augmented expression of collagen-I and fibronectin in the ECM, were greatly increased in birds with WB. Wooden breast myopathy upregulated expressions of transforming growth factor-beta (TGF-β) and the phosphorylation of Smad 2 and 3, thereby activating TGF-β-mediated Smad signaling pathway, which further enhanced the transcription of profibrotic mediators. In addition, regulators involved in collagen biosynthesis and cross-linking including prolyl 4-hydroxylase, lysyl oxidase, lysyl hydroxylase, and decorin were increased in the WB muscle. Finally, the expressions of both matrix metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) were increased in the WB muscle, which might be related with reduced ECM remodeling. Overall, WB myopathy induces severe fibrosis by enhancing ECM deposition and collagen cross-linking in the PM muscle of broiler chickens, possibly via the activation of TGF-β signaling and the dysregulation of the MMP and TIMP system.

The Role of Stromal Proteolytic Systems in Cancer Progression (Review)

Oncological diseases belong to life-threatening pathologies being the second most frequent cause of morbidity and mortality after cardiovascular diseases. Clarification of carcinogenesis mechanisms makes it possible to expand the stock of tools available for prevention of critical illness accompanying this pathological condition.Nowadays, proteolytic systems of tumor microenvironment (ТМЕ) are regarded as key regulators of a tumor progression including tumor growth, invasion and metastazing. The review discusses ТМЕ structure and role in cancer progression.Recent data decipher the role of proteolytic systems in the interaction stromal cells with tumor cells in different types of cancer in humans. The most known proteolytic systems contributed to cancer progression are matrix metalloproteinase system (MMP), urokinase-type plasminogen activator system (uPA-system), various cathepsins, granzymes, and elastase. Inhibition of extracellular proteolysis in the course of an oncological process is considered an effective approach to cancer therapy.

Tamoxifen-induced alterations in the expression of selected matrix metalloproteinases (MMP-2, -9, -10, and −13) and their tissue inhibitors (TIMP-2 and -3) in the chicken ovary

Matrix metalloproteinases (MMPs) are a family of peptidases that disintegrate extracellular matrix (ECM) molecules associated with tissue remodeling, including reproductive tissues. Their actions are largely controlled by specific tissue inhibitors of MMPs (TIMPs). The role and regulation of MMPs in the chicken ovary is largely unknown. The aim of the present study was to examine the effect of tamoxifen (TMX; estrogen receptor modulator) treatment on the expression of selected members of the MMP system in the laying hen ovary. The activity of MMP-2 and -9 was also examined. Real-time polymerase chain reaction and western blot analyses revealed changes in mRNA and/or protein expression of MMP-2, -9, -10, −13, TIMP-2, and TIMP-3 in the following ovarian follicles after TMX treatment: white (WF), yellowish (YF), small yellow (SYF), and the largest yellow preovulatory (F3–F1). The response to TMX depended on the stage of follicle development and the layer of follicular wall. Moreover, ovarian regression following TMX treatment was accompanied by both an increase in total activity of MMP-2 in the theca layer of F3–F2 and granulosa layer of F2, and a decrease in total activity of MMP-2 in the WF, YF, and SYF, and MMP-9 in theca of F3–F1. In conclusion, the TMX-induced changes in MMP-2, -9, -10, and -13, and TIMP-2 and -3 mRNA expression, as well as MMP-2 and -9 activity, were dependent on tissue and the stage of follicular maturation. Our findings strongly suggests a role for estrogen in regulating the transcription, translation, and/or posttranslational activity of members of the MMP system. Further, these components may be involved in the orchestration of ECM turnover and cellular functions during ovary regression, which occur under conditions of reduced estrogenic activity.

The Matrix Metalloproteinase System in Colorectal Cancer Progression and 15-year Survival

The Matrix Metalloproteinase System in Colorectal Cancer Progression and 15-year Survival

Understanding the complexity of the matrix metalloproteinase system and its relevance to age-related diseases: Age-related macular degeneration and Alzheimer's disease.

Extracellular matrices (ECMs) are maintained by tightly coupled processes of continuous synthesis and degradation. The degradative arm is mediated by a family of proteolytic enzymes called the matrix metalloproteinases (MMPs). These enzymes are released as latent proteins (pro-MMPs) and on activation are capable of degrading most components of an ECM. Activity of these enzymes is checked by the presence of tissue inhibitors of MMPs (TIMPs) and current opinion holds that the ratio of TIMPs/MMPs determines the relative rate of degradation. Thus, elevated ratios are thought to compromise degradation leading to the accumulation of abnormal ECM material, whilst diminished ratios are thought to lead to excessive ECM degradation (facilitating angiogenesis and the spread of cancer cells). Our recent work has shown this system to be far more complex. MMP species tend to undergo covalent modification leading to homo- and hetero-dimerization and aggregation resulting in the formation of very large macromolecular weight MMP complexes (LMMCs). In addition, the various MMP species also show a bound-free compartmentalisation. The net result of these changes is to reduce the availability of the latent forms of MMPs for the activation process. An assessment of the degradation potential of the MMP system in any tissue must therefore take into account the degree of sequestration of the latent MMP species, a protocol that has not previously been addressed. Taking into consideration the complexities already described, we will present an analysis of the MMP system in two common neurodegenerative disorders, namely age-related macular degeneration (AMD) and Alzheimer's disease (AD).

Matrix Metalloproteinases System and Types of Fibrosis in Rat Heart during Late Pregnancy and Postpartum.

Background and objectives: Cardiac remodeling in pregnancy and postpartum is poorly understood. The aim of this study was to evaluate changes in cardiac fibrosis (pericardial, perivascular, and interstitial), as well as the expression of matrix metalloproteinases (MMP-1, MMP-2, and MMP-9) and their inhibitors (Tissue inhibitors of metalloproteinases, TIMP-1 and TIMP-4) during late pregnancy and postpartum in rat left ventricle. Materials and Methods: Female Sprague–Dawley rats were used for this study. Rats were divided three groups: non-pregnant, late pregnancy, and postpartum. The heart was weighed and cardiac fibrosis was studied by conventional histological procedures. The expression and transcript level of target proteins were evaluated using immunoblot techniques and quantitative PCR. Results: The experiments showed an increase of perivascular, pericardial, and interstitial fibrosis in heart during pregnancy and its reversion in postpartum. Moreover, in late pregnancy, MMP-1, MMP-2, and MMP-9 metalloproteinases were downregulated and TIMP-1 and TIMP-4 were upregulated in left ventricle. Conclusions: Our data suggest that the metalloproteinases system is involved in the cardiac extracellular matrix remodeling during pregnancy and its reversion in postpartum, this improves the knowledge of the adaptive cardiac remodeling in response to a blood volume overload present during pregnancy.

MMP20 Single-Nucleotide Polymorphisms Correlate with Susceptibility to Alcohol-Induced Osteonecrosis of the Femoral Head in Chinese Males.

BackgroundAlcohol-induced osteonecrosis of the femoral head (ONFH) is caused by the interaction of genetic and environmental factors. Genetic variations of matrix metalloproteinase (MMP) system are associated with ONFH development and progression. In this study, we aimed to evaluate the relationships between MMP20 gene polymorphisms and the risk of alcohol-induced ONFH in Chinese Han males.Material/MethodsIn this case-control study, genotypes of 14 selected SNPs in the MMP20 gene were assayed using MassARRAY in 299 male cases with alcohol-induced ONFH and in 197 healthy males. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the influence of gene polymorphism on occurrence of alcohol-induced ONFH by allelic model analysis, genotype model analysis and haplotype analysis.ResultsAfter allelic model analysis, the minimum alleles of rs10895322, rs1784424, rs3781788, and rs1573954 correlated with an increased risk of alcohol-induced ONFH (P<0.05). Genetic model analysis revealed significant associations of 9 SNPs with alcohol-induced ONFH occurrence even after adjustment for age (P<0.05): 2 protective SNPs (rs1711423 and rs1784418) and 7 high-risk SNPs (rs10895322, rs1784424, rs3781788, rs7126560, rs1573954, rs1711399, and rs2292730). Moreover, 8 SNPs showed a statistically significant association with different clinical phenotypes (P<0.05). Beyond that, haplotype “CGGTTCCA” in MMP20 was discovered to correlate with a 1.63-fold increased risk of alcohol-induced ONFH (OR: 1.63, 95% CI: 1.15–2.30, P=0.0058).ConclusionsOur data sheds new light on the associations of MMP20 gene polymorphisms with alcohol-induced ONFH predisposition in Chinese Han males.