Use Of Matrix Metalloproteinases Inhibitors Research Articles

ПРИМЕНЕНИЕ ИНГИБИТОРОВ МЕТАЛЛОПРОТЕИНАЗ В КОМПЛЕКСНОМ ЛЕЧЕНИИ ВОСПАЛИТЕЛЬНЫХ ЗАБОЛЕВАНИЙ ПАРОДОНТА

Periodontitis is the most common inflammatory disease that leads to the destruction of the supporting tissues of the tooth. Therapeutic treatments aimed at reducing the effects of matrix metalloproteinases (MMPs) may be an effective adjunct to the treatment of periodontitis. The review examines the role of proteolytic enzyme inhibitors in the treatment of inflammatory periodontal diseases. General information about the ability of tetracyclines to inhibit MMPs is discussed. The purpose of the study was to examine the use of MMP inhibitors as a treatment for periodontal disease. Material and research methods. A scientific review of studies was carried out in Russian and English using information portals and platforms eLIBRARY.ru, Web of Science, PubMed and Scopus. The search was carried out using the following keywords: matrix metalloproteinases; oral diseases; tissue inhibitors of metalloproteinases. Of the 55 initially identified articles, after the initial analysis, 19 publications devoted to the study of MMP inhibitors associated with periodontal diseases were selected. Results of the study. Analysis of the literature allows us to conclude that the elimination of local irritants of periodontal tissues, the use of a therapeutic and prophylactic complex of measures using MMP inhibitors will have an advantage over traditional methods of treatment, will contribute to longer remission and prevent the progression of the inflammatory process in periodontal tissues, positively influence its course and reduce treatment time. The use of metalloproteinase inhibitors is an effective therapeutic strategy in the treatment of periodontal diseases. Conclusions. The therapeutic potential of metalloproteinase inhibitors may help prevent tissue damage in inflammatory periodontal diseases.

Physiological and Pathophysiological Aspects of Diabetic Foot Ulcer and its Treatment Strategies.

Diabetes foot ulcers (DFU) are among the most common complications in diabetic patients, leading to amputation and psychological distress. This mini-review covers the general physiology of ulcer healing as well as the pathophysiology of DFU and its therapies. Only a few treatments have been sanctioned and numerous compounds from various pharmacological groups are now being tested at various stages for the prevention and treatment of DFUs. The main objective of this mini-review is to give concise information on how diabetes mellitus impairs the healing of chronic ulcers by disrupting numerous biological systems of the normal healing process, resulting in diabetic foot ulceration, and the current therapeutic approaches. A review of accessible material from systemic searches in the PubMed/Medline, Scopus, Cochrane Database of Systematic Reviews, published review articles, and Clinical Trials databases (US National Library of Medicine) with no period of limitation was conducted. The treatment of DFUs comprises wound dressings, use of matrix metalloproteinase inhibitors in wound dressing, antibiotics, skin substitutes, pressure off-loading growth factors and stem cells, gene therapy, topical oxygen therapy, etc. Conclusion: The majority of these treatments are aimed at treating diabetic foot ulcers and preventing diabetic wounds from becoming infected. Yet, there is no single therapy that can be advised for diabetic foot ulcer patients. Future treatment strategies should be considered an appropriate treatment option for persistent wounds.

Matrix metalloproteinases as therapeutic targets in breast cancer.

Matrix metalloproteinases (MMPs) are the most prominent proteinases involved in tumorigenesis. They were initially recognized to promote tumor progression by remodeling the extracellular matrix through their proteolytic activity. However, accumulating evidence has revealed that some MMPs have protective roles in cancer progression, and the same MMP can exert opposing roles depending on the cell type in which it is expressed or the stage of cancer. Moreover, studies have shown that MMPs are involved in cancer progression through their roles in other biological processes such as cell signaling and immune regulation, independent of their catalytic activity. Despite the prognostic significance of tumoral or stromal expression of MMPs in breast cancer, their roles and molecular mechanisms in breast cancer progression remain unclear. As the failures of early clinical trials with broad-spectrum MMP inhibitors were mainly due to a lack of drug specificity, substantial efforts have been made to develop highly selective MMP inhibitors. Some recently developed MMP inhibitory monoclonal antibodies demonstrated promising anti-tumor effects in preclinical models of breast cancer. Importantly, anti-tumor effects of these antibodies were associated with the modulation of tumor immune microenvironment, suggesting that the use of MMP inhibitors in combination with immunotherapy can improve the efficacy of immunotherapy in HER2-positive or triple-negative breast cancer. In this review, the current understanding of the roles of tumoral or stromal MMPs in breast cancer is summarized, and recent advances in the development of highly selective MMP inhibitors are discussed.

Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology.

The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix metalloproteinases are proteases capable of remodeling the extracellular matrix. More recently, MMPs have been demonstrated to play numerous additional biologic roles in cell signaling, immune regulation, and transcriptional control, all of which are unrelated to the degradation of the extracellular matrix. In this review, we will present milestones and major discoveries of MMP research, including various clinical trials for the use of MMP inhibitors. We will discuss the reasons behind the failures of most MMP inhibitors for the treatment of cancer and inflammatory diseases. There are still misconceptions about the pathophysiological roles of MMPs and the best strategies to inhibit their detrimental functions. This review aims to discuss MMPs in preclinical models and human pathologies. We will discuss new biochemical tools to track their proteolytic activity in vivo and ex vivo, in addition to future pharmacological alternatives to inhibit their detrimental functions in diseases. SIGNIFICANCE STATEMENT: Matrix metalloproteinases (MMPs) have been implicated in most inflammatory, autoimmune, cancers, and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progression and resolution. Thousands of MMP substrates have been suggested, and a few hundred have been validated. After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases.

EFFECTIVENESS OF MATRIX METALLOPROTEINASES INHIBITORS FOR PREVENTIVE TREATMENT OF GENERALIZED PERIODONTITIS

Generalized periodontitis is one of the most widespread human stomatological diseases; it is diagnosed in 11.0 % of the world's population. Despite the recognition of the microbial factor as leading in its etiopathogenesis, antimicrobial treatment of gingivitis, added with removal of dental plaque, does not prevent the further development of periodontitis. Dysbacteriosis causes inflammation which leads to an increase of proteolysis products. They are a nutrient medium for periodontal pathogenic microflora, they contribute to its growth. So, the use of anti-inflammatory drugs, such as matrix metalloproteinase inhibitors, is promising for preventive treatment of generalized periodontitis.
 The aim of the work is to conduct a clinical trial of complex treatment which includes matrix
 metalloproteinase inhibitors in patients with diffuse gingivitis and generalized periodontitis of chronic course.
 Materials and methods of the research. 60 patients with chronic course of diffuse gingivitis and generalized periodontitis of initial, I and II stages, were treated. The effectiveness of the treatment was evaluated in the early and distant term (after 1 year) according to data of the clinical and radiological examination, computer tomography, biochemical examination of oral fluid for matrix metalloproteinases-8 and -9 (MMP-8, -9) and immunohistochemical study of gingival biopsies for cytoplasmic expression of matrix metalloproteinase-1 (MMP-1).
 Results of the research. According to the data of the clinical examination, complete elimination of inflammatory symptoms in periodontal tissues was achieved in 93.3% of patients in the comparison group in 12-14 days and in 96.7% in the base group in 10-12 days. In patients in whom the developed therapeutic scheme was used, the best dynamics of the index assessment of the state of hygiene, gingiva and periodontal complex was established. The main difference between the research groups was the preservation of obtained results in 1 year after treatment in patients of the base group (p ˂ 0.05). In particular, a year later, the results of bone mineral density measurement for patients of the base group did not change from baseline, while in the comparison group there was their significant decrease (p ˂ 0.05), indicating the progression of inflammatory-destructive process in periodontal tissues.
 After treatment, a significant reduction in the level of MMP-8 and MMP-9 in the oral fluid of patients of both groups was achieved (p ˂ 0.05). In patients of the base group, in contrast to the comparison, these results were the same in the distant term (p ˂ 0.05). When assessing the cytoplasmic expression of MMP-1 in epithelial and stromal cells after treatment, zero result was in 96.7% of patients in the base group and in 80.0% – in the comparison group, and after 1 year – in 90.0% vs 63.3% respectively.
 It should be noted that the differences between the base and comparison groups were most observed for patients with gingivitis and generalized periodontitis of initial stage without destructive processes in periodontal tissues. It suggests the greatest effectiveness of the proposed treatment in the early stages of pathological process.
 Thus, based on the fact that the activity of matrix metalloproteinases characterizes the course of the inflammatory process in periodontal tissues, a decrease in their level according to biochemical and immunohistochemical studies in the base group against the comparison indicates a better anti-inflammatory effect of the developed treatment to prevent the progression of generalized periodontitis.
 Conclusion. The obtained results allow recommending the use of matrix metalloproteinase inhibitors as a preventive pathogenetic treatment for the patients with chronical course of gingivitis and generalized periodontitis of the initial stage, to inhibit the inflammatory component of the pathological process.
 Prospects for further research. It should be studied the indication for repeated courses of matrix metalloproteinase inhibitors in patients with periodontal disease.

STRUCTURE AND FUTURE PROSPECTIVE OF MATRIX METALLOPROTEINASES

Matrix metalloproteinases (MMPs) are group of enzymes responsible for the collagen, and protein degradation in extracellular matrix (ECM). Collagen is the main structural component of connective tissue, and its degradation is an important process in the tissue development, remodeling, and repair. MMP family is divided into 6 groups: collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and non-classified MMPs. The MMPs, and MMP inhibitors (MMPI) have multiple biological functions in stages of cancer development. MMPs, and MMPI are extensively examined as potential anticancer medications. The need for selective and metabolically stable MMPs and MMP inhibitors determined the effect of their activity on biological systems. In particular, the relationship of MMPs with the immune system has revealed the potential for the use of MMP inhibitors in therapy. As is known, the degree of invasive growth and metastasis of tumor cells are determined by their ability to cleave all ECM structures of the extracellular matrix - only MMPs can do this. It is important to note that ECM affects the behavior of both cancer cells and stromal, endothelial and immune cells in the environment. The fundamentally important role of ECM is dynamism during tissue homeostasis and the ability to regulate the activation of immune cells.

Inhibition of matrix metalloproteinases: a troubleshooting for dentin adhesion.

Matrix metalloproteinases (MMPs) are enzymes that can degrade collagen in hybrid layer and reduce the longevity of adhesive restorations. As scientific understanding of the MMPs has advanced, useful strategies focusing on preventing these enzymes' actions by MMP inhibitors have quickly developed in many medical fields. However, in restorative dentistry, it is still not well established. This paper is an overview of the strategies to inhibit MMPs that can achieve a long-lasting material-tooth adhesion. Literature search was performed comprehensively using the electronic databases: PubMed, ScienceDirect and Scopus including articles from May 2007 to December 2019 and the main search terms were “matrix metalloproteinases”, “collagen”, and “dentin” and “hybrid layer”. MMPs typical structure consists of several distinct domains. MMP inhibitors can be divided into 2 main groups: synthetic (synthetic-peptides, non-peptide molecules and compounds, tetracyclines, metallic ions, and others) and natural bioactive inhibitors mainly flavonoids. Selective inhibitors of MMPs promise to be the future for specific targeting of preventing dentin proteolysis. The knowledge about MMPs functionality should be considered to synthesize drugs capable to efficiently and selectively block MMPs chemical routes targeting their inactivation in order to overcome the current limitations of the therapeutic use of MMPs inhibitors, i.e., easy clinical application and long-lasting effect.

Matrix Metalloproteases as Influencers of the Cells' Social Media.

Matrix metalloproteinases (MMPs) have been studied in the context of cancer due to their ability to increase cell invasion, and were initially thought to facilitate metastasis solely through the degradation of the extracellular matrix (ECM). MMPs have also been investigated in the context of their ECM remodeling activity in several acute and chronic inflammatory diseases. However, after several MMP inhibitors failed in phase III clinical trials, a global reassessment of their biological functions was undertaken, which has revealed multiple unanticipated functions including the processing of chemokines, cytokines, and cell surface receptors. Despite what their name suggests, the matrix aspect of MMPs could contribute to a lesser part of their physiological functions in inflammatory diseases, as originally anticipated. Here, we present examples of MMP substrates implicated in cell signaling, independent of their ECM functions, and discuss the impact for the use of MMP inhibitors.

Matrix metalloproteinases in the CNS: interferons get nervous.

Matrix metalloproteinases (MMPs) have been investigated in context of chronic inflammatory diseases and demonstrated to degrade multiple components of the extracellular matrix (ECM). However, following several disappointing MMP clinical trials, recent studies have demonstrated unexpected novel functions of MMPs in viral infections and autoimmune inflammatory diseases in unanticipated locations. Thus, MMPs play additional functions in inflammation than just ECM degradation. They can regulate the activity of chemokines and cytokines of the immune response by precise proteolytic processing resulting in activation or inactivation of signaling pathways. MMPs have been demonstrated to cleave multiple substrates of the central nervous systems (CNS) and contribute to promoting and dampening diseases of the CNS. Initially, believed to be solely promoting pathologies, more than 10 MMPs to date have been shown to have protective functions. Here, we present some of the beneficial and destructive roles of MMPs in CNS pathologies and discuss strategies for the use of MMP inhibitors.

Pathological and therapeutic aspects of matrix metalloproteinases: Implications in osteosarcoma.

Osteosarcoma (OS) is one of the most common malignant bone tumors in children and adolescents, and the eighth leading form of childhood cancer. Matrix metalloproteinases (MMPs) are proteolytic enzymes implicated in certain cancers including OS. In this review, we discuss the mechanism of actions of MMPs in progression of OS, and the therapeutic use of MMPs inhibitors in the treatment of OS with subsequent clinical studies and future management. The expression of MMPs is upregulated in cancer cells by a variety of cytokines and growth factors, and upregulation of MMPs induces degradation of the extracellular matrix that contributes to cell proliferation by releasing growth factors. MMPs promote the detachment and migration of endothelial cells, cross the basement membrane as well as invade the surrounding lymphatic vessels and causes cancer metastasis. The use of selective MMP inhibitors with limited side effects might be promising therapeutic strategy in the treatment of OS. More clinical trials are necessary to evaluate the role of selective MMPs inhibitors in the prevention and treatment of OS along with their assessment of toxicity.

Modulation of MMP-2 and MMP-9 secretion by cytokines, inducers and inhibitors in human glioblastoma T-98G cells.

Brain tumors are highly aggressive, characterized by the secretion of high levels of matrix metalloproteinase (MMP)-2 and MMP-9 that degrade the extracellular matrix and basement membrane, allowing cancer cells to spread to distal organs. Various cytokines, mitogens, growth factors, inducers and inhibitors control MMP activity. We investigated the roles of these in the regulation of MMP-2 and MMP-9 in human glioblastoma T-98G cells. Human T-98G cells were grown in DME supplemented with 15% fetal bovine serum and antibiotics in 24-well tissue culture plates. At near confluence, cells were washed with phosphate-buffered saline and incubated in serum-free media with: phorbol12-myristate 13-acetate (PMA) at 10, 25, 50 and 100ng/ml; tumor necrosis factor (TNF)-α and interleukin (IL)-1β at 0.1, 1, 10 and 25ng/ml; lipopolysaccharide (LPS) at 10, 25, 50 and 100µg/ml; epigallocatechin gallate (EGCG) and doxycycline (Dox) at 10, 25, 50 and 100µM without and with PMA; a nutrient mixture (NM) containing lysine, proline, ascorbic acid and green tea extract without and with PMA at 10, 50, 100, 500 and 1,000µg/ml; actinomycinD and cyclohexamide at 2and4µM; retinoic acid and dexamethasone at 50µM. After 24h the media were removed and analyzed for MMP-2 and MMP-9 by zymography and densitometry. Glioblastoma T-98G cells expressed only one band corresponding to MMP-2. PMA treatment showed increased MMP-2 and MMP-9 secretions up to 25ng/ml and decreased levels of secretions at 50and100ng/ml, with no significant overall effect. TNF-α induced an up and down effect on MMP-2 and a slight induction of MMP-9. IL-1β demonstrated a slight dose-dependent increase in T-98G secretion of MMP-2, but no induction of MMP-9. LPS showed dose-dependent decreased inactive MMP-2 secretion, increased active MMP-2 secretion and no effect on MMP-9. EGCG, Dox and NM, without and with PMA, downregulated the expression of MMP-2 and MMP-9 in a dose-dependent manner. ActinomycinD, cyclohexamide, retinoic acid and dexamethasone also had inhibitory effects on MMP-2. Our results showed that cytokines, mitogens and inhibitors modulated T-98G cell MMP-2 and MMP-9 expression, suggesting the clinical use of MMP inhibitors, particularly such potent and non-toxic ones as the nutrient mixture and its component EGCG in the management of glioblastoma cancers.

Cytokines, inducers and inhibitors modulate MMP-2 and MMP‑9 secretion by human Fanconi anemia immortalized fibroblasts.

Acute myeloid leukemia and head and neck squamous cell carcinomas are the major causes of mortality and morbidity in Fanconi anemia (FA) patients. Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, have been implicated in tumor invasion and metastasis. Various cytokines, mitogens, growth factors, inducers and inhibitors control MMP activities. We investigated the roles of these in the regulation of MMP-2 and MMP-9 in human immortalized fibroblasts from FA. Human FA immortalized fibroblast cell lines FA-A:PD220 and FA-D2:PD20 were grown in minimum essential medium (MEM) supplemented with 15% fetal bovine serum (FBS) and antibiotics in 24-well tissue culture plates. At near confluence, the cells were washed with phosphate‑buffered saline (PBS) and incubated in serum-free media with the following: phorbol 12-myristate 13-acetate (PMA) at 10-100ng/ml; tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) at 0.1-25ng/ml; lipopolysaccharide (LPS) at 10-100µg/ml; epigallocatechin gallate (EGCG) and doxycycline (Dox) at 10-100µM without and with PMA; a nutrient mixture (NM) without and with PMA at 10-1,000µg/ml; actinomycin-D and cyclohexamide at 2and4µM; retinoic acid and dexamethasone at 50µM. After 24h, media were removed and analyzed for MMP-2 and MMP-9 by zymography. Both FA cell lines expressed only MMP-2 and responded similarly to cytokines, mitogens, inducers and inhibitors. PMA potently stimulated MMP-9 and had a moderate effect on MMP-2. TNF-α showed variable effects on MMP-2 and significantly enhanced MMP-9. IL-1β enhanced MMP-2 slightly and MMP-9 significantly. LPS had a moderate stimulatory effect on MMP-2 and no effect on MMP-9. EGCG, Dox and NM, without and with PMA, downregulated MMP-2 and MMP-9 expression. Actinomycin-D, retinoic acid and dexamethasone also had inhibitory effects on MMP-2. Our results showed that cytokines, mitogens and inhibitors modulated FA fibroblast MMP-2 and MMP-9 expression, suggesting the clinical use of MMP inhibitors, particularly such potent and non-toxic ones as the NM and its component EGCG in the management of FA cancers.

Targeted drug delivery to emphysematous lungs: Inhibition of MMPs by doxycycline loaded nanoparticles

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in U.S. following cancer and heart disease. Current hypothesis regarding mechanism of emphysema suggest that chronic exposure to cigarette smoke and particulate matter causes irritation in the alveoli and this triggers an inflammatory response. This response attracts a host of inflammatory cells like macrophages, neutrophils, and lymphocytes. Cytokines, reactive oxygen species, prostaglandins, leukotrienes, proteases mediate the progression of the disease [1, 2]. Of particular interest to this research is emphysema in COPD patients. This results in poorly reversible airway obstruction due to the destruction of alveoli and elastin fibers in the lung [3, 4]. Loss of elastin in the lungs correlates to loss of lung function in patients [5, 6]. Currently available treatments for COPD aim at only providing temporary relief to the patients by mitigating inflammation or by the action of bronchodilators [7–10]. Corticosteroids have been shown to have no anti-inflammatory effect in COPD patients [11]. None of the available treatments has shown promising effect on treating the disease yet. Matrix metalloproteinases (MMPs) have received a lot of attention in emphysema research with their key role in damaging elastin fibers, thus contributing to the enlargement of air spaces and loss of elastic recoil in the lungs [12]. Use of MMP inhibitors in COPD has been explored in animal models [13, 14] but there is always the risk of off-targeting of MMPs with the systemic delivery of these drugs [15]. Doxycycline is one potential broad-spectrum MMP inhibitor. It is the only FDA approved MMP inhibitor that is widely available. It is shown to inhibit early inflammation in diseases like pulmonary fibrosis [16, 17] by reducing MMP activity in smooth muscle cells [18, 19]. It can also be used as a treatment for COPD exacerbations. While the exact process of MMP inhibition by doxycycline (or tetracyclines in general) is not known, it is believed that this happens by both direct inhibition of MMPs and by inhibiting their expression. Direct inhibition involves chelation of bivalent ions like Ca2+ or Zn2+ which are essential for the functioning of these enzymes [20]. Liu et al., [18] observed reduced MMP-2 mRNA half life but steady state MMP-2 mRNA production by human smooth muscle cells (SMCs) in vitro, there by proposing a post-transcriptional destabilization of MMP-2 mRNA by doxycycline. Additionally, doxycycline specifically targets endothelial cells where it inhibits MMP synthesis [21]. Nanoparticles have recently been investigated as potential drug delivery systems to the lungs because of various advantages they offer [22]. In order to increase the specificity and availability of nanoparticles loaded with drugs, use of monoclonal antibodies to specific biomolecules within the lungs has been suggested as a potential opportunity but has been poorly explored [23, 24]. Inhalation of drug-loaded particulates via aerosols is common way to deliver drugs to the lungs. However, inhalation of drugs to treat pulmonary disorders has certain limitations. The fate of an inhaled particle depends on its size, anatomy of airways and ventilatory parameters [25–27]. Despite the plethora of drug delivery opportunities available, there is a greater need for a highly effective delivery method, which combines an active targeting formulation and consistent local release of a drug for enhanced therapeutic effect. In this paper, we investigated a novel method of drug delivery, in a rat elastase model of emphysema, with a systemic injection of nanoparticles loaded with doxycycline, an MMP inhibitor. We took advantage of elastin damage in emphysema and tested our hypothesis that anti-elastin coated bovine serum albumin (BSA) nanoparticles injected intravenously will target the lungs and will release doxycycline over a period to suppress MMP activity in lungs.

A Divalent PAMAM-Based Matrix Metalloproteinase/Carbonic Anhydrase Inhibitor for the Treatment of Dry Eye Syndrome.

Synthetic sulfonamide derivatives are a class of potent matrix metalloproteinase inhibitors (MMPI) that have potential for the treatment of diseases related to uncontrolled expression of these enzymes. The lack of selectivity of the large majority of such inhibitors, leading to the inhibition of MMPs in tissues other than the targeted one, has dramatically reduced the therapeutic interest in MMPIs. The recent development of efficient drug delivery systems that allow the transportation of a selected drug to its site of action has opened the way to new perspectives in the use of MMPIs. Here, a PAMAM-based divalent dendron with two sulfonamidic residues was synthesized. This nanomolar inhibitor binds to the catalytic domain of two MMPs as well as to the transmembrane human carbonic anhydrases (hCAs) XII, which is present in the eye and considered an antiglaucoma target. In the animal model of an experimental dry eye, no occurrence of dotted staining in eyes treated with our inhibitor was observed, indicating no symptoms of corneal desiccation.

Impact on ovulatory parameters with the use of MMP inhibitors in PCOS, MI-PCOS: a pilot study

PolycysticOvary Syndrome (PCOS) is characterized in part by anovulation and excess ovarian androgen mediated by excess LH. Wepreviously reported LH induced steroid production in freshly isolated murine ovarian follicles requires transactivation of the EGF receptor following release of EGF-like ligands by matrix metalloproteinases (MMPs). This steroidogenesis is suppressed by doxycycline (DOXY), anagent known to inhibit MMP2/9(1). Furthermore, we have shown that the addition of the MMP inhibitor Galardin to prenatally androgenized mice improved cycling.

A role for matrix remodelling proteins in invasive and malignant meningiomas.

Meningiomas are one of the most common brain tumours in adults. Invasive and malignant meningiomas present a significant therapeutic challenge due to high recurrence rates and invasion into surrounding bone, brain, neural and soft tissues. Understanding the molecular mechanism of invasion could help in designing novel therapeutic approaches in order to prevent the need for repeat surgery, decrease morbidity and improve patient survival. The aim of this study was to identify the key factors and underlying mechanisms which govern invasive properties of meningiomas. Formalin-fixed paraffin-embedded (FFPE) as well as frozen tumour tissues from bone-invasive, non-invasive and malignant meningiomas were used for RNA microarray, quantitative real-time PCR or Western blot analyses. Malignant meningioma cell lines (F5) were subject to MMP16 downregulation or overexpression and used for in vitro and in vivo functional assays. Subdural xenograft meningioma tumours were generated to study the invasion of tumour cells into brain parenchyma using cell lines with altered MMP16 expression. We establish that the expression level of MMP16 was significantly elevated in both bone-invasive and brain invasive meningiomas. Gain- and loss-of-function experiments indicated a role for MMP16 in meningioma cell movement, invasion and tumour cell growth. Furthermore, MMP16 was shown to positively regulate MMP2, suggesting this mechanism may modulate meningioma invasion in invasive meningiomas. Overall, the results support a role for MMP16 in promoting invasive properties of the meningioma tumours. Further studies to explore the potential value for clinical use of matrix metalloproteinases inhibitors are warranted.

MMP Inhibitors on Dentin Stability

The aim of this study was to systematically review the literature for in vitro and ex vivo studies that evaluated the effect of matrix metalloproteinase (MMP) inhibitors during the adhesive procedure on the immediate and long-term resin-dentin bond strength. The search was conducted in 6 databases with no publication year or language limits, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. From 1,336 potentially eligible studies, 48 were selected for full-text analysis, and 30 were included for review, with 17 considered in the meta-analysis. Two reviewers independently selected the studies, extracted the data, and assessed the risk of bias. Pooled effect estimates were expressed as the weighted mean difference between groups. The most used MMP inhibitor was chlorhexidine (CHX). Immediate bond strength results showed no difference between 2% CHX and control; however, a difference was found between 0.2% CHX and control at baseline. After aging, CHX presented higher bond strength values compared to control groups (p < .05). However, this was not observed for longer periods of aging. High heterogeneity was found in some comparisons, especially for the water storage aging subgroup. Subgroup analyses showed that self-etching and etch-and-rinse adhesives are benefited by the CHX use. From the studies included, only 1 presented low risk of bias, while the others showed medium or high risk of bias. The use of MMP inhibitors did not affect the immediate bond strength overall, while it influenced the aged bond strength. Aging procedures influenced bond strength values of the dentin adhesion stability.

MMP inhibition as a potential method to augment the healing of skeletal muscle and tendon extracellular matrix

The extracellular matrix (ECM) of skeletal muscle and tendon is composed of different types of collagen molecules that play important roles in the transmission of forces throughout the body, and in the repair and regeneration of injured tissues. Fibroblasts are the primary cells in muscle and tendon that maintain, repair, and modify the ECM in response to mechanical loading, injury, and inactivity. Matrix metalloproteinases (MMPs) are enzymes that digest collagen and other structural molecules, which are synthesized and excreted by fibroblasts. MMPs are required for baseline ECM homeostasis, but disruption of MMP regulation due to injury or disease can alter the normal ECM architecture and prevent proper force transmission. Chronic injuries and diseases of muscles and tendons can be severely debilitating, and current therapeutic modalities to enhance healing are quite limited. This review will discuss the mechanobiology of MMPs, and the potential use of MMP inhibitors to improve the treatment of injured and diseased skeletal muscle and tendon tissue.

Expression of matrix metalloproteinases and their inhibitors in the woodchuck model of hepatocellular carcinoma

Matrix metalloproteinases (MMPs) play a central role in tumor invasion and metastasis. Increased expression of MMPs occurs during development of hepatocellular carcinoma (HCC) in humans following infection with hepatitis B virus (HBV). Woodchucks are used as an animal model for hepadnavirus-induced HCC. All woodchucks infected chronically with woodchuck hepatitis virus (WHV), a virus that is closely related to HBV, develop HCC. In the present study MMPs and related molecules were investigated in woodchucks to better understand the mechanisms of extracellular matrix remodeling in HCC. Three groups of samples were studied: liver and HCC tissues from animals infected with WHV and age- and gender-matched normal liver from animals not infected with WHV. New partial gene sequences for woodchuck MMP-2, MMP-7, and MMP-9 as well as their inhibitors NGAL, TIMP-1, and TIMP-2 were identified and used for determination of expression levels in liver and HCC by qRT-PCR. Compared to liver of WHV-naïve woodchucks, high levels of MMP-1, MMP-2, MMP-7, NGAL, and TIMP-1 were detected in liver of animals infected with WHV. However, no differences were found for TIMP-2. MMP-9 expression was higher in HCC than in liver of animals not infected with WHV. Immunohistochemical staining demonstrated that MMP-9 immunoreactivity was most intense in HCC, correlating with the progression of liver disease. Upregulation of MMP-9 in HCC was confirmed by Western blotting and zymography analysis. Furthermore, the activity of woodchuck MMPs was suppressed by BiPS, a common inhibitor of mammalian MMPs. These results suggest the use of MMP inhibitors as a potential HCC treatment strategy that could be explored in woodchucks.

Matrix metalloproteinase (MMP)-2 gene polymorphisms affect circulating MMP-2 levels in patients with migraine with aura

Matrix metalloproteinases (MMP) are involved in the disruption of blood–brain barrier (BBB) during migraine attacks. In the present study, we hypothesized that two functional polymorphisms (C−1306T and C−735T) in MMP-2 gene and MMP-2 haplotypes are associated with migraine and modify MMP-2 and tissue inhibitor of MMP (TIMP)-2 levels in migraine. Genotypes for MMP-2 polymorphisms were determined by real time-PCR using Taqman allele discrimination assays. Haplotypes were inferred using the PHASE program. Plasma MMP-2 and TIMP-2 concentrations were measured by gelatin zymography and ELISA, respectively, in 148 healthy women without history of migraine and in 204 women with migraine (153 without aura; MWA, and 51 with aura; MA). Patients with MA had higher plasma MMP-2 concentrations and MMP-2/TIMP-2 ratios than patients with MWA and controls (P<0.05). While MMP-2 genotype and haplotype distributions for the polymorphisms were similar among the groups (P>0.05), we found that the CC genotype for C−735T polymorphism and the CC haplotype were associated with higher plasma MMP-2 concentrations in MA group (P<0.05). Our findings may help to understand the role of MMP-2 and its genetic variants in the pathophysiology of migraine and to identify a particular group of migraine patients with increased MMP-2 levels that would benefit from the use of MMP inhibitors.