Noninvasive Assessment of Liver Fibrosis: Current and Future Clinical and Molecular Perspectives.

Liver fibrosis is one of the risk factors for hepatocellular carcinoma (HCC) development. The staging of liver fibrosis can be evaluated only via a liver biopsy, which is an invasive procedure. Noninvasive methods for the diagnosis of liver fibrosis can be divided into morphological tests such as elastography and serum biochemical tests. Transient elastography is reported to have excellent performance in the diagnosis of liver fibrosis and has been accepted as a useful tool for the prediction of HCC development and other clinical outcomes. Two-dimensional shear wave elastography is a new technique and provides a real-time stiffness image. Serum fibrosis markers have been studied based on the mechanism of fibrogenesis and fibrolysis. In the healthy liver, homeostasis of the extracellular matrix is maintained directly by enzymes called matrix metalloproteinases (MMPs) and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs). MMPs and TIMPs could be useful serum biomarkers for liver fibrosis and promising candidates for the treatment of liver fibrosis. Further studies are required to establish liver fibrosis-specific markers based on further clinical and molecular research. In this review, we summarize noninvasive fibrosis tests and molecular mechanism of liver fibrosis in current daily clinical practice.

Matrix Metalloproteinases in Renal Diseases: A Critical Appraisal.

Matrix metalloproteinases (MMPs) are endopeptidases within the metzincin protein family that not only cleave extracellular matrix (ECM) components, but also process the non-ECM molecules, including various growth factors and their binding proteins. MMPs participate in cell to ECM interactions, and MMPs are known to be involved in cell proliferation mechanisms and most probably apoptosis. These proteinases are grouped into six classes: collagenases, gelatinases, stromelysins, matrilysins, membrane type MMPs, and other MMPs. Various mechanisms regulate the activity of MMPs, inhibition by tissue inhibitors of metalloproteinases being the most important. In the kidney, intrinsic glomerular cells and tubular epithelial cells synthesize several MMPs. The measurement of circulating MMPs can provide valuable information in patients with kidney diseases. They play an important role in many renal diseases, both acute and chronic. This review attempts to summarize the current knowledge of MMPs in the kidney and discusses recent data from patient and animal studies with reference to specific diseases. A better understanding of the MMPs' role in renal remodeling may open the way to new interventions favoring deleterious renal changes in a number of kidney diseases.

Matrix Metalloproteases in Arterial Hypertension and their Trend after Antihypertensive Treatment.

BACKGROUND/AIMS: Arterial hypertension is characterized by vascular remodelling, atherosclerosis and cardiovascular complications. Matrix metalloproteases (MPPs) are endopeptidases produced by all the cells present in the vascular wall and are involved in the regulation of the extracellular matrix protein turnover. MMPs contribute to blood vessel formation, remodelling, angiogenesis; whereas an altered expression or activity of MMPs or their tissue inhibitors (TIMPs) results correlated with the development and progression of cardiovascular complications. METHODS: We examined the literature data regarding the role of MMPs in human hypertension, including their involvement in vascular remodelling, and the effects of some antihypertensive molecules on these MMP/TIMP profile. RESULTS: The expression and the activity of some MMPs and TIMPs are impaired in human hypertension. An altered MMPs/TIMPs balance plays an important role in the vascular wall rearrangement, in response to hemodynamic changes which may induce myocardial hypertrophy and fibrosis leading to ventricular remodelling. Several studies have examined the effects of some antihypertensive molecules, such as ACE inhibitors, angiotensin receptor blockers, calcium-channel blockers, and aldosterone antagonists, on the MMPs/TIMPs profile by obtaining positive results. CONCLUSION: Considering the data taken into consideration, the authors believe that in clinical practice a strategic antihypertensive therapy directed to the MMPs profile, may be useful to decrease the risk of cardiovascular complications.

The role of metalloproteinases in endometrial remodelling during menstrual cycle.

Endometrium is the only tissue in the human body subject to cyclic transformations under the influence of ovarian steroid hormones. As estradiol and progesterone balance throughout the physiological menstrual cycle changes, so does the expression of metalloproteinases (MMPs). These endopeptides are responsible for keeping the balance between the process of synthesis and degradation of extracellular matrix proteins. Thus, MMP's take part in sustaining physiological stability of the endometrium. A number of MMPs found in the endometrial tissue and their activity is related to menstrual cycle phase. This paper is an up-to-date review of literature of Medline database. The search was conducted for key words including "matrix metalloproteinases", "MMPs", "TIMPs" and "tissue inhibitors of metalloproteinases". Over 1092 publications regarding interdependence and interplay between ovarian hormones and the role of various MMPs and their inhibitors in normal endometrial remodelling and in pathological conditions were analysed and critically reviewed.

Crosstalk between TGF-ß signaling and miRNAs in breast cancer metastasis.

Transforming growth factor-ß (TGF-ß) signaling pathway is a key regulator of various cancer biologies, including cancer cell migration, invasion, angiogenesis, proliferation, as well as apoptosis, and it is one of indispensable signaling pathways during cancer metastasis. TGF-ß signaling pathway can regulate and be regulated by a series of molecular and signaling pathways where microRNAs (miRNAs) seem to play important roles. miRNAs are small non-coding RNAs that can regulate expressions of their target genes. Emerging evidence suggest that miRNAs participate in various biological and pathologic processes such as cancer cells apoptosis, proliferation, invasion, migration, and metastasis by influencing multiple signaling pathways. In this article, we focus on the interaction between miRNAs and TGF-ß in breast cancer (BC) metastasis through modulating invasion-metastasis-related factors, including epithelial-to-mesenchymal transition (EMT), cancer stem cells (CSCs), matrix metalloproteinase (MMP), tissue inhibitors of MMPs (TIMPs), cell adhesion molecules (CAMs), and tumor microenvironment (TME). Through a clear understanding of the complicated links between TGF-ß pathway and miRNAs, it may provide a novel and safer therapeutic target to prevent BC metastasis.

Tissue inhibitor of metalloproteases-4 (TIMP-4) modulates adipocyte differentiation in vitro.

Tissue inhibitors of metalloproteases (TIMPs) are multifunctional proteins that inhibit matrix metalloproteases (MMPs). The latest described member of the family, TIMP-4, is expressed mainly in adipose tissue, with detectable levels in the brain and heart. Besides its high expression in fat, the role of this inhibitor in adipose tissue is unknown. In order to study the role of TIMP-4 during adipogenesis in vitro, 3T3-L1 cells were stably transfected with a TIMP-4 specific shRNA or a control shRNA. Unexpectedly, upon TIMP-4 knockdown, 3T3-L1 cells differentiated faster into mature adipocytes. To get better insight of TIMP-4's role in adipogenesis, microarray expression analyses were performed. Network enrichment analyses uncovered 25 significant upstream signaling pathways, among which the NFκB cascade was found. Previous works have shown that NFκB is a key regulator of adipogenesis. In accordance, we found that TIMP-4 knockdown decreased NFκB activity during adipogenesis. The present work suggests that TIMP-4 might act as a negative regulator of adipogenesis through NFκB cascade modulation.

TGF-ß1 and TIMP-4 regulate atrial fibrosis in atrial fibrillation secondary to rheumatic heart disease.

To investigate the involvement of transforming growth factor-ß1 (TGF-ß1) and tissue inhibitor of metalloproteinase 4 (TIMP-4) in influencing the severity of atrial fibrosis in rheumatic heart disease (RHD) patients with atrial fibrillation (AF). The degree of myocardial fibrosis was evaluated using Masson staining. The expression levels of TGF-ß1, TIMP-4, matrix metalloproteinase-2 (MMP-2), type I collagen, and type III collagen were estimated by Western blot analysis. Additionally, TGF-ß1 and TIMP-4 mRNA levels were quantified by qRT-PCR. The effect of TGF-ß1 stimulation on TIMP-4 expression was assessed by in vitro stimulation of freshly isolated human atrial fibroblasts with recombinant human TGF-ß1, followed by Western blot analysis to detect changes in TIMP-4 levels. Masson stain revealed that the left atrial diameter and collagen volume fraction were obviously increased in AF patients, compared to sinus rhythm (SR) controls (both P < 0.05). Western blot analysis showed significantly elevated levels of the AF markers MMP-2, type I collagen, and type III collagen in the AF group, in comparison to the SR controls (all P < 0.05). In the AF group, TGF-ß1 expression was relatively higher, while TIMP-4 expression was apparently lower than the SR group (all P < 0.05). TIMP-4 expression level showed a negative association with TGF-ß1 expression level (r = -0.98, P < 0.01) and TGF-ß1 stimulation of atrial fibroblasts led to a sharp decrease in TIMP-4 protein level. Increased TGF-ß1 expression and decreased TIMP-4 expression correlated with atrial fibrosis and ECM changes in the atria of RHD patients with AF. Notably, TGF-ß1 suppressed TIMP-4 expression, suggesting that selective TGF-ß1 inhibitors may be useful therapeutic agents.

Regulation of matrix metalloproteinases activity studied in human endometrium as a paradigm of cyclic tissue breakdown and regeneration.

When abundant and activated, matrix metalloproteinases (MMPs, or matrixins) degrade most, if not all, constituents of the extracellular matrix (ECM). The resulting massive tissue breakdown is best exemplified in humans by the menstrual lysis and shedding of the endometrium, the mucosa lining the uterus. After menstruation, MMP activity needs to be tightly controlled as the endometrium regenerates and differentiates to avoid abnormal tissue breakdown while allowing tissue repair and fine remodelling to accommodate implantation of a blastocyst. This paper reviews how MMPs are massively present and activated in the endometrium at menstruation, and how their activity is tightly controlled at other phases of the cycle. Progesterone represses expression of many but not all MMPs. Its withdrawal triggers focal expression of MMPs specifically in the areas undergoing lysis, an effect mediated by local cytokines such as interleukin-1α, LEFTY-2, tumour necrosis factor-α and others. MMP-3 is selectively expressed at that time and activates proMMP-9, otherwise present in latent form throughout the cycle. In addition, a large number of neutrophils loaded with MMPs are recruited at menstruation through induction of chemokines, such as interleukin-8. At the secretory phase, progesterone repression of MMPs is mediated by transforming growth factor-ß. Tissue inhibitors of metalloproteinases (TIMPs) are abundant at all phases of the cycle to prevent any undue MMP activity, but are likely overwhelmed at menstruation. At other phases of the cycle, MMPs can elude TIMP inhibition as exemplified by recruitment of active MMP-7 to the plasma membrane of epithelial cells, allowing processing of membrane-associated growth factors needed for epithelial repair and proliferation. Finally, receptor-mediated endocytosis through low density lipoprotein receptor-related protein-1 (LRP-1) efficiently clears MMP-2 and -9 at the proliferative and secretory phases. This mechanism is probably essential to prevent any excessive ECM degradation by the active form of MMP-2 that is permanently present. However, shedding of the ectodomain of LRP-1 specifically at menstruation prevents endocytosis of MMPs allowing full degradation of the ECM. Thus endometrial MMPs are regulated at the levels of transcription, release from infiltrating neutrophils, activation, binding to the cell membrane, inhibition by TIMPs and endocytic clearance by LRP-1. This allows tight control during endometrial growth and differentiation but results in a burst of activity for menstrual tissue breakdown. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.

An alternate perspective on the roles of TIMPs and MMPs in pathology.

Tissue inhibitors of metalloproteinases (TIMPs) are pleiotropic extracellular proteins. TIMPs are recognized as endogenous regulators of matrix metalloproteinases (MMPs), a large family of extracellular enzymes with proteolytic activities that participate in cellular homeostasis, adaptation, and tissue remodeling. In addition to their roles as endogenous potent MMP inhibitors, accumulating evidence indicates important physiological roles for TIMPs that are independent of their ability to block MMP activities. For instance, MMP-independent actions of TIMP-1 in the central nervous system have been implicated in synaptic plasticity, neuroprotection, oncogenesis, and oligodendrocyte differentiation. Expression of TIMP-1 is dramatically increased in response to a variety of injurious and inflammatory insults. In the context of disease pathogenesis, MMP and TIMP expression are interpreted with respect to the proteolytic consequences of increased MMP/TIMP ratios. Here, we provide an alternative perspective on the homeostatic balance of TIMP and MMP proteins, whereby consideration is given to the possible role of MMPs as cognate inhibitors of the signaling functions of TIMPs. Thus, MMPs may regulate the receptor-mediated actions of TIMPs, inasmuch as TIMPs are themselves inhibitors of MMP-mediated proteolytic activities. This broader view reflects our emerging understanding that TIMP signaling and MMP inhibition represent two important functions of TIMPs that have the potential to affect tissue pathology.

Hypoxia inhibits cardiomyocyte proliferation in fetal rat hearts via upregulating TIMP-4.

Maternal hypoxia inhibits cardiomyocyte proliferation in the heart of fetal and neonatal rats. The present study tested the hypothesis that hypoxia has a direct effect inhibiting cardiomyocyte proliferation via upregulating tissue inhibitors of metalloproteinases (TIMP) in fetal rat hearts. Isolated fetal rat hearts and rat embryonic ventricular myocyte H9c2 cells were treated ex vivo with 20% or 1% O(2) for 48 or 24 h, respectively. Hypoxia caused a significant reduction in cardiomyocyte Ki-67 expression and bromodeoxyuridine incorporation in fetal hearts and H9c2 cells. In both fetal hearts and H9c2 cells, hypoxia resulted in a significant decrease in a cell division marker cyclin D2 but an increase in a cell division inhibitor p27. Additionally, hypoxia caused an upregulation of TIMP-3 and TIMP-4 in fetal hearts and H9c2 cells. Knockdown of TIMP-3 in H9c2 cells significantly increased cyclin D2 and Ki-67 and partially blocked the hypoxia-induced inhibition of cyclin D2 and Ki-67 in H9c2 cells. Unlike TIMP-3, TIMP-4 knockdown had no significant effects on the basal levels of cell proliferation but completely abrogated the hypoxia-mediated effects. These findings provide evidence of a novel causal role of TIMP-4 and TIMP-3 in the direct inhibitory effect of hypoxia on cardiomyocyte proliferation in the developing heart.

Matrix metalloproteinases: do they play a role in mucosal pathology of the oral cavity?

Matrix metalloproteinases (MMPs) are critical factors in maintaining the integrity of mucosa and mediating normal biological processes. An imbalance between tissue levels of these mediators and their natural inhibitors is believed to underlie the pathophysiology of many diseases, including those affect the gastrointestinal and oral mucosae. The ongoing development of synthetic inhibitors of these mediators may provide opportunities to develop treatment modalities for patients suffering from these diseases. Understanding the role of MMPs in the pathophysiology of many diseases, however, is far from complete, and the improvement of pharmaceutical management strategies can only be achieved if the underlying process of these diseases is completely comprehended. This paper reviews the functions of matrix metalloproteinases and addresses their role in mediating mucosal pathologies with emphasis on oral mucosa.

Lower incidence of hepatic metastases of colorectal cancer in patients with chronic liver diseases: meta-analysis.

BACKGROUND/AIMS: The rarity of metastatic malignancy in injured liver has been noticed. This meta-analysis evaluates the difference in occurrence of metastatic colorectal cancer in healthy and chronically injured liver. METHODOLOGY: Literature search of occurrence of metastatic colorectal cancer in chronically injured liver opposed to healthy liver was conducted. Chronically injured/damaged liver included cirrhosis, steatosis or fatty liver and infection with Hepatitis virus B or C. RESULTS: A total of 7 retrospective studies between 1992 and 2010 matched the selection criteria with total of 4049 patients. Results suggest significantly lower incidence of colorectal metastasis in chronically injured liver (Pooled odds ratio = 0.260 (95% CI = 0.18 to 0.38); χ² (test odds ratio differs from 1) = 45.90 (df = 1); p <0.0001). CONCLUSIONS: Patients with chronic liver injury have significantly lower occurrence of hepatic metastasis of primary colorectal cancer than the patients with healthy liver.

Matrix metalloproteinases in arthritis: towards precision medicine.

Proteolysis of structural molecules of the extracellular matrix (ECM) is an irreversible post-translational modification in all arthropathies. Common joint disorders, including osteoarthritis and rheumatoid arthritis, have been associated with increased levels of matrix remodelling enzymes, including matrix metalloproteinases (MMPs). MMPs, in concert with other host proteinases and glycanases, destroy proteoglycans, collagens and other ECM molecules. MMPs may also control joint remodelling indirectly by signalling through cell-surface receptors or by proteolysis of cytokines and receptor molecules. After synthesis as pro-forms, MMPs can be activated by various types of post-translational modifications, including proteolysis. Once activated, MMPs are controlled by general and specific tissue inhibitors of metalloproteinases (TIMPs). In rheumatoid arthritis, proteolysis of the ECM results in so-called remnant epitopes that enhance and perpetuate autoimmune processes in susceptible hosts. In osteoarthritis, the considerable production of MMP-13 by chondrocytes, often concurrent with mechanical overload, is a key event. Hence, information about the regulation, timing, localization and activities of MMPs in specific disease phases and arthritic entities will help to develop better diagnostics. Insights into beneficial and detrimental effects of MMPs on joint tissue inflammation are also necessary to plan and execute (pre)clinical studies for better therapy and precision medicine with MMP inhibitors. With the advances in proteomics and single-cell transcriptomics, two critical points need attention: neglected neutrophil MMP biology, and the analysis of net proteolytic activities as the result of balances between MMPs and their inhibitors.

The history of matrix metalloproteinases: milestones, myths, and misperceptions.

Since the discovery of tadpole collagenase in 1962, the matrix metalloproteinase (MMP) family has emerged as a significant proteinase group with recognized effects on the cardiovascular system. Over the last 40 years, many milestones have been achieved, from the identification of the first MMP, to the generation of the first MMP cDNA clone and null mouse, to the clinical approval of the first MMP inhibitor. Over the years, a few myths and misunderstandings have interwoven into the truths. In this review, we will discuss the major milestones of MMP research, as well as review the misinterpretations and misperceptions that have evolved. Clarifying the confusions and dispelling the myths will both provide a better understanding of MMP properties and functions and focus the cardiovascular field on the outstanding research questions that need to be addressed.

Tumor-recruited neutrophils and neutrophil TIMP-free MMP-9 regulate coordinately the levels of tumor angiogenesis and efficiency of malignant cell intravasation.

Tumor-associated neutrophils contribute to neovascularization by supplying matrix metalloproteinase-9 (MMP-9), a protease that has been genetically and biochemically linked to induction of angiogenesis. Specific roles of inflammatory neutrophils and their distinct proMMP-9 in the coordinate regulation of tumor angiogenesis and tumor cell dissemination, however, have not been addressed. We demonstrate that the primary tumors formed by highly disseminating variants of human fibrosarcoma and prostate carcinoma recruit elevated levels of infiltrating MMP-9-positive neutrophils and concomitantly exhibit enhanced levels of angiogenesis and intravasation. Specific inhibition of neutrophil influx by interleukin 8 (IL-8) neutralization resulted in the coordinated diminishment of tumor angiogenesis and intravasation, both of which were rescued by purified neutrophil proMMP-9. However, if neutrophil proMMP-9, naturally devoid of tissue inhibitor of metalloproteinases (TIMP), was delivered in complex with TIMP-1 or in a mixture with TIMP-2, the protease failed to rescue the inhibitory effects of anti-IL8 therapy, indicating that the TIMP-free status of proMMP-9 is critical for facilitating tumor angiogenesis and intravasation. Our findings directly link tumor-associated neutrophils and their TIMP-free proMMP-9 with the ability of aggressive tumor cells to induce the formation of new blood vessels that serve as conduits for tumor cell dissemination. Thus, treatment of cancers associated with neutrophil infiltration may benefit from specific targeting of neutrophil MMP-9 at early stages to prevent ensuing tumor angiogenesis and tumor metastasis.

The role of selected metalloproteinases in cheiroarthropathy in children with type 1 diabetes - a pilotage study.

BACKGROUND: Metalloproteinases of the external matrix play an important role in ethiopatogenesis of diabetic complications especially in microangiopathy and also in fibrosing processes with occurrence the cheiroarthropathy, but clinical data are insufficient. AIMS: The aim of the study was to assess the influence of metalloproteinases such as gelatinase A (MMP2) and gelatinase B (MMP9), and their tissue inhibitors (TIMP2, TIMP9) in ethiopathogenesis of cheiroatrhopathy in children with diabetes type 1. MATERIALS AND METHODS: Forty one children were observed in average age of 14.98 years (±3.03 years), with the average duration of diabetes 6.78 years (±3.21 years), and with average HbA1c within all diabetes duration time 7.1% (6.47-7.5%). In all patients, the occurrence of cheiroarthropathy was checked, and concentration of metalloproteinase's and their inhibitors in serum were measured using ELISA method. Probe was divided into two groups because of presence of cheiroarthropathy. The comparing analysis of these two groups was conducted, and the correlation between metalloproteinase's concentration and their tissue inhibitors with selected parameters was done. RESULTS: When comparing group with cheiroarthropathy (n = 19) with the group without cheiroarthropathy (n = 22), the statistically significant elevated levels of metalloproteinase's were proved such as: MMP2 - 202 ng/ml (193-207) vs. 138 ng/ml (130-158), p < 0.001; MMP9 - 462 ng/ml (426-505) vs. 288 ng/ml (251-313), 0.001; TIMP2 - 182 ng/ml (177-190) vs. 104 ng/ml (88-165), p < 0.001); TIMP9 - 85 ng/ml (68-95) vs. 55 ng/ml (50-60), p < 0.001. There was no correlation between occurrence of cheiroarthropathy and age of the diabetes onset, duration of diabetes, grade of metabolic compensation, insulin dosages, weight and height. CONCLUSION: In children with long-term diabetes, although relatively metabolic compensation, the cheiroarthropathy has been occurred accompanying by elevated concentrations of metalloproteinase's and their tissue inhibitors. The presence of cheiroarthropathy could be treated as a simple test to identification the patients endangered to develop chronic vascular complication.

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion.

Cells adhere to one another and/or to matrices that surround them. Regulation of cell-cell (intercellular) and cell-matrix adhesion is tightly controlled in normal cells, however, defects in cell adhesion are common in the majority of human cancers. Multilateral communication among tumor cells with the extracellular matrix (ECM) and neighbor cells is accomplished through adhesion molecules, ECM components, proteolytic enzymes and their endogenous inhibitors. There is sufficient evidence to suggest that reduced adherence is a tumor cell property engaged during tumor progression. Tumor cells acquire the ability to change shape, detach and easily move through spaces disorganizing the normal tissue architecture. This property is due to changes in expression levels of adhesion molecules and/or due to elevated levels of secreted proteolytic enzymes, including matrix metalloproteinases (MMPs). Among other roles, MMPs degrade the ECM and, therefore, prepare the path for tumor cells to migrate, invade and spread to distant secondary areas, where they form metastasis. Tissue inhibitors of metalloproteinases or TIMPs control MMP activities and, therefore, minimize matrix degradation. Both MMPs and TIMPs are involved in tissue remodeling and decisively regulate tumor cell progression including tumor angiogenesis. In this review, we describe and discuss data that support the important role of MMPs and TIMPs in cancer cell adhesion and tumor progression.

The dual roles of three MMPs and TIMP in innate immunity and metamorphosis in the silkworm, Bombyx mori.

The matrix metalloproteinases (MMPs) and their endogenous inhibitory factors, tissue inhibitors of metalloproteinases (TIMPs), are implicated in many diseases. However, the mammalian MMPs (> 20) and TIMPs (> 3) are larger in number, and so little is known about their individual roles in organisms. Hence, we have systematically studied the roles of all three MMPs and one TIMP in silkworm innate immunity and metamorphosis. We observed that MMPs and TIMP are highly expressed during the pupation stage of the silkworms, and TIMP could interact with each MMPs. High-activity MMPs and low-activity TIMP may enhance the infection of B. mori nucleopolyhedrovirus in both in vitro and in vivo. MMPs' knockout and TIMP overexpression delayed silkworm development and even caused death. Interestingly, different MMPs' knockout led to different tubular tissue dysplasia. These findings provide insights into the conserved functions of MMPs and TIMP in human organogenesis and immunoregulation.

Metzincin proteases and their inhibitors: foes or friends in nervous system physiology?

Members of the metzincin family of metalloproteinases have long been considered merely degradative enzymes for extracellular matrix molecules. Recently, however, there has been growing appreciation for these proteinases and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs), as fine modulators of nervous system physiology and pathology. Present all along the phylogenetic tree, in all neural cell types, from the nucleus to the synapse and in the extracellular space, metalloproteinases exhibit a complex spatiotemporal profile of expression in the nervous parenchyma and at the neurovascular interface. The irreversibility of their proteolytic activity on numerous biofactors (e.g., growth factors, cytokines, receptors, DNA repair enzymes, matrix proteins) is ideally suited to sustain structural changes that are involved in physiological or postlesion remodeling of neural networks, learning consolidation or impairment, neurodegenerative and neuroinflammatory processes, or progression of malignant gliomas. The present review provides a state of the art overview of the involvement of the metzincin/TIMP system in these processes and the prospects of new therapeutic strategies based on the control of metalloproteinase activity.

Mice with tissue inhibitor of metalloproteinases 4 (Timp4) deletion succumb to induced myocardial infarction but not to cardiac pressure overload.

Tissue inhibitor of metalloproteinases 4 (TIMP4) is expressed highly in heart and found dysregulated in human cardiovascular diseases. It controls extracellular matrix remodeling by inhibiting matrix metalloproteinases (MMPs) and is implicated in processes including cell proliferation, apoptosis, and angiogenesis. Timp4-deficient mice (Timp4(-/-)) were generated to assess TIMP4 function in normal development and in models of heart disease. We deleted exons 1-3 of the Timp4 gene by homologous recombination. Timp4(-/-) mice are born healthy, develop normally, and produce litters of normal size and gender distribution. These mice show no compensation by overexpression of Timp1, Timp2, or Timp3 in the heart. Following cardiac pressure overload by aortic banding, Timp4(-/-) mice have comparable survival rate, cardiac histology, and cardiac function to controls. In this case, Timp4 deficiency is compensated by increased cardiac Timp2 expression. Strikingly, the induction of myocardial infarction (MI) leads to significantly increased mortality in Timp4(-/-) mice primarily due to left ventricular rupture. The post-MI mortality of Timp4(-/-) mice is reduced by administration of a synthetic MMP inhibitor. Furthermore, combining the genetic deletion of Mmp2 also rescues the higher post-MI mortality of Timp4(-/-) mice. Finally, Timp4(-/-) mice suffer reduced cardiac function at 20 months of age. Timp4 is not essential for murine development, although its loss moderately compromises cardiac function with aging. Timp4(-/-) mice are more susceptible to MI but not to pressure overload, and TIMP4 functions in its capacity as a metalloproteinase inhibitor after myocardial infarction.