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The matrix metalloproteinase (MMP) family belongs to the metzincin clan of zinc-dependent metallopeptidases. Due to their enormous implications in physiology and disease, MMPs have mainly been studied in vertebrates. They are engaged in extracellular protein processing and degradation, and present extensive paralogy, with 23 forms in humans. One characteristic of MMPs is a ~165-residue catalytic domain (CD), which has been structurally studied for 14 MMPs from human, mouse, rat, pig and the oral-microbiome bacterium Tannerella forsythia. These studies revealed close overall coincidence and characteristic structural features, which distinguish MMPs from other metzincins and give rise to a sequence pattern for their identification. Here, we reviewed the literature available on MMPs outside vertebrates and performed database searches for potential MMP CDs in invertebrates, plants, fungi, viruses, protists, archaea and bacteria. These and previous results revealed that MMPs are widely present in several copies in Eumetazoa and higher plants (Tracheophyta), but have just token presence in eukaryotic algae. A few dozen sequences were found in Ascomycota (within fungi) and in double-stranded DNA viruses infecting invertebrates (within viruses). In contrast, a few hundred sequences were found in archaea and >1000 in bacteria, with several copies for some species. Most of the archaeal and bacterial phyla containing potential MMPs are present in human oral and gut microbiomes. Overall, MMP-like sequences are present across all kingdoms of life, but their asymmetric distribution contradicts the vertical descent model from a eubacterial or archaeal ancestor. This article is part of a Special Issue entitled: Matrix Metalloproteinases edited by Rafael Fridman.
According to the growth state of hair follicles, the hair cycle is divided into the anagen, catagen and telogen phases. A number of biological factors have been shown to synchronize with the hair cycle. As an important component of the hair follicle, the extracellular matrix is regulated by matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitor of matrix metalloproteinases; TIMPs). It has been reported that MMP-2, MMP-9 and TIMP-1 are associated with the hair cycle; however, their expression levels during the hair cycle have not been fully elucidated. Reverse transcription-polymerase chain reaction and ELISA analysis in the present study demonstrated that, during the hair cycle in mice, mRNA and protein expression levels of MMP-2 and MMP-9 were elevated in the anagen phase, and decreased during the catagen and telogen phases. Furthermore, SDS-PAGE gelatin zymography demonstrated that their activities fluctuated in the hair cycle. Additionally, it was observed that the mRNA and protein expression levels of TIMP-1 and TIMP-2 were negatively correlated with MMP-9 and MMP-2, respectively. Immunohistochemical examination demonstrated that MMP-2 and TIMP-2 were present in all structures of the hair follicle. However, MMP-9 and TIMP-1 were locally expressed in certain areas of the hair follicle, such as in the sebaceous gland at the anagen, catagen and telogen phases, and in the inner root sheath at the catagen phase. These results suggested that MMP-2 and MMP-9 may serve an important role in the hair growth cycle.
Around the world diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD), which is characterized by mesangial expansion, glomerulosclerosis, tubular atrophy, and interstitial fibrosis. The hallmark of the pathogenesis of DKD is an increased extracellular matrix (ECM) accumulation causing thickening of the glomerular and tubular basement membranes, mesangial expansion, sclerosis, and tubulointerstitial fibrosis. The matrix metalloproteases (MMPs) family are composed of zinc-dependent enzymes involved in the degradation and hydrolysis of ECM components. Several MMPs are expressed in the kidney; nephron compartments, vasculature and connective tissue. Given their important role in DKD, several studies have been performed in patients with DKD proposing that the measurement of their activity in serum or in urine may become in the future markers of early DKD. Studies from diabetic nephropathy experimental models suggest that a balance between MMPs levels and their inhibitors is needed to maintain renal homeostasis. This review focuses in the importance of the MMPs within the kidney and their modifications at the circulation, kidney and urine in patients with DKD. We also cover the most important studies performed in experimental models of diabetes in terms of MMPs levels, renal expression and its down-regulation effect.
Matrix metalloproteinases (MMP) are key players in the remodelling of the extracellular matrix under physiological and pathological conditions. Thermodynamic parameters of human recombinant metalloproteinases of the active (rMMP2, 3, 7, 8 and 9) and latent (rPro-MMP2, 3 and 9) forms were obtained by differential scanning calorimetry (DSC). Temperature by itself does not result in autocatalysis of recombinant MMP. The transitions observed by DSC correspond to structural domains of the monomeric protein. In this study, we show the domain organization of these proteins, where the thermal transition (Tm) of the main component is observed at 71.3 °C (ProMMP-2); 74.8 °C (ProMMP-8); 80.0 °C (ProMMP-3); 92.6 °C (ProMMP-9) and 98.3 °C (ProMMP-7). For MMP-3, this main Tm is related to the catalytic domain (CD). The isolated recombinant CD of MMP-3 unfolds as a single transition at Tm 83.4 °C, matching the more stable domain observed in the full-length active form of rMMP-3. The denaturation profile of rProMMP-3 shows the main transition at Tm 80 °C, a less stable domain before the propeptide domain (PD) cleavage. Our results indicate that the structural stability of MMP and particularly their CD are not substantially altered after cleavage of the PD. We propose that the thermodynamic parameters obtained by DSC are relevant for the functional study of MMP, particularly to reveal their contribution in complex biological samples in health and disease.
Structural vascular changes in two-kidney, one-clip (2K-1C) hypertension may result from increased matrix metalloproteinase (MMP)-2 activity. MMP-2 activation is regulated by other MMPs, including transmembrane-MMPs, and by tissue inhibitors of MMPs (TIMPs). We have investigated the localization of MMP-2, -9, -14, and TIMPs 1-4 in hypertensive aortas and measured their levels by zymography/Western blotting and immunohistochemistry. Gelatinolytic activity was assayed in tissues by in situ zymography. Sham-operated and 2K-1C hypertensive rats were treated with doxycycline (or vehicle) for 8 weeks, and the systolic blood pressure was monitored weekly. Doxycycline attenuated 2K-1C hypertension (165 + or - 11.7 mmHg versus 213 + or - 7.9 mm Hg in hypertensive controls, P<0.01), and completely prevented increase in the thicknesses of the media and the intima in 2K-1C animals (P<0.01). Increased amounts of MMP-2, -9, and -14 were found in hypertensive aortas, as well as enhanced gelatinolytic activity. A gradient in the localization of MMP-2, -9, and -14 was found, with increased amounts detected in the intima, at sites with higher gelatinolytic activity. Doxycycline attenuated hypertension induced increases in all the 3 investigated MMPs in both the media and the intima (all P<0.05), but it did not change the amounts of TIMPs 1-4 (P>0.05). Therefore, an imbalance between increased amounts of MMPs at the tissue level without a corresponding increase in the quantities of TIMPs, particularly in the intima and inner media layers, appears to account for the increased proteolytic activity found in 2K-1C hypertension-induced maladaptive vascular remodeling.
Echinoderms are one of the most ancient groups of invertebrates. The study of their genomes has made it possible to conclude that these animals have a wide variety of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). The phylogenetic analysis shows that the MMPs and TIMPs underwent repeated duplication and active divergence after the separation of Ambulacraria (Echinodermata+Hemichordata) from the Chordata. In this regard the homology of the proteinases and their inhibitors between these groups of animals cannot be established. However, the MMPs of echinoderms and vertebrates have a similar domain structure. Echinoderm proteinases can be structurally divided into three groups-archetypal MMPs, matrilysins, and furin-activatable MMPs. Gelatinases homologous to those of vertebrates were not found in genomes of studied species and are probably absent in echinoderms. The MMPs of echinoderms possess lytic activity toward collagen type I and gelatin and play an important role in the mechanisms of development, asexual reproduction and regeneration. Echinoderms have a large number of genes encoding TIMPs and TIMP-like proteins. TIMPs of these animals, with a few exceptions, have a structure typical for this class of proteins. They contain an NTR domain and 10-12 conservatively located cysteine residues. Repeated duplication and divergence of TIMP genes of echinoderms was probably associated with an increase in the functional importance of the proteins encoded by them in the physiology of the animals.
Fibrosis--a debilitating condition that can occur in most organs - is characterized by excess deposition of a collagen-rich extracellular matrix (ECM). At first sight, the activities of proteinases that can degrade matrix, such as matrix metalloproteinases (MMPs), might be expected to be under-expressed in fibrosis or, if present, could function to resolve the excess matrix. However, as we review here, some MMPs are indeed anti-fibrotic, whereas others can have pro-fibrotic functions. MMPs modulate a range of biological processes, especially processes related to immunity and tissue repair and/or remodeling. Although we do not yet know precisely how MMPs function during fibrosis--that is, the protein substrate or substrates that an individual MMP acts on to effect a specific process--experiments in mouse models demonstrate that MMP-dependent functions during fibrosis are not limited to effects on ECM turnover. Rather, data from diverse models indicate that these proteinases influence cellular activities as varied as proliferation and survival, gene expression, and multiple aspects of inflammation that, in turn, impact outcomes related to fibrosis.
Mouse hepatitis virus (MHV; m-β-CoV) serves as a useful model for studying the cellular factors involved in neuroinflammation. To understand the role of matrix metalloproteinases (MMPs) in neuroinflammation, brain tissues from m-β-CoV-infected mice were harvested at different days post-infection (d.p.i) and investigated for Mmp expression by RT-qPCR. Mmp-2, -3, -8, -12 showed significant mRNA upregulation peaking with viral replication between 5 and 6 d.p.i. Elevated levels of MMP regulator TIMP-1 are suggestive of a TIMP-1 mediated host antiviral response. Biological network assessment suggested a direct involvement of MMP-3, -8, -14 in facilitating peripheral leukocyte infiltrations. Flow cytometry confirmed the increased presence of NK cells, CD4+ and CD8+ T cells, neutrophils, and MHCII expressing cells in the m-β-CoV infected mice brain. Our study revealed that m-β-CoV upregulated Park7, RelA, Nrf2, and Hmox1 transcripts involved in ROS production and antioxidant pathways, describing the possible nexus between oxidative pathways, MMPs, and TIMP in m-β-CoV-induced neuroinflammation.
Dentin is primarily composed of hydroxyapatite crystals within a rich organic matrix. The organic matrix comprises collagenous structural components, within which a variety of bioactive molecules are sequestered. During caries progression, dentin is degraded by acids and enzymes derived from various sources, which can release bioactive molecules with potential reparative activity towards the dentin-pulp complex. While these molecules' repair activities in other tissues are already known, their biological effects are unclear in relation to degradation events during disease in the dentin-pulp complex. This study was undertaken to investigate the effects of dentin matrix components (DMCs) that are partially digested by matrix metalloproteinases (MMPs) in vitro and in vivo during wound healing of the dentin-pulp complex. DMCs were initially isolated from healthy dentin and treated with recombinant MMPs. Subsequently, their effects on the behaviour of primary pulp cells were investigated in vitro and in vivo. Digested DMCs modulated a range of pulp cell functions in vitro. In addition, DMCs partially digested with MMP-20 stimulated tertiary dentin formation in vivo, which exhibited a more regular tubular structure than that induced by treatment with other MMPs. Our results indicate that MMP-20 may be especially effective in stimulating wound healing of the dentin-pulp complex.
Age-related macular degeneration (AMD) is a complex, multifactorial and progressive retinal disease affecting millions of people worldwide. In developed countries, it is the leading cause of vision loss and legal blindness among the elderly. Although the pathogenesis of AMD is still barely understood, recent studies have reported that disorders in the regulation of the extracellular matrix (ECM) play an important role in its etiopathogenesis. The dynamic metabolism of the ECM is closely regulated by matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). The present review focuses on the crucial processes that occur at the level of the Bruch's membrane, with special emphasis on MMPs, TIMPs, and the polymorphisms associated with increased susceptibility to AMD development. A systematic literature search was performed, covering the years 1990-2020, using the following keywords: AMD, extracellular matrix, Bruch's membrane, MMPs, TIMPs, and MMPs polymorphisms in AMD. In both early and advanced AMD, the pathological dynamic changes of ECM structural components are caused by the dysfunction of specific regulators and by the influence of other regulatory systems connected with both genetic and environmental factors. Better insight into the pathological role of MMP/TIMP complexes may lead to the development of new strategies for AMD treatment and prevention.
Reduced β(2)-glycoprotein I (reduced β(2)GP I), which has free sulfhydryl groups, is present in plasma and serum; it can protect vascular endothelial cells from damage due to oxidative stress in vitro. We investigated the effects of reduced β(2)GP I on the expression of various matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in the aortas of diabetic mice.
The proteoglycan biglycan (BGN) is involved in collagen fibril assembly and its fragmentation is likely to be associated with collagen turnover during the pathogenesis of diseases which involve dysregulated extracellular matrix remodeling (ECMR), such as rheumatoid arthritis (RA) and liver fibrosis. The scope of the present study was to develop a novel enzyme-linked immunosorbent assay (ELISA) for the measurement of a MMP-9 and MMP-12-generated biglycan neo-epitope and to test its biological validity in a rat model of RA and in two rat models of liver fibrosis, chosen as models of ECMR.
Matrix metalloproteinases (MMPs) are key biological mediators of processes as diverse as wound healing, embryogenesis, and cancer progression. Although MMPs may be induced through multiple signaling pathways, the precise mechanisms for their regulation in cancer are incompletely understood. Because cytoskeletal changes are known to accompany MMP expression, we sought to examine the potential role of the poorly understood cytoskeletal protein, nestin, in modulating melanoma MMPs. Nestin knockdown (KD) upregulated the expression of specific MMPs and MMP-dependent invasion both through extracellular matrix barriers in vitro and in peritumoral connective tissue of xenografts in vivo. The development of three-dimensional melanospheres that in vitro partially recapitulate noninvasive tumorigenic melanoma growth was inhibited by nestin KD, although ECM invasion by aberrant melanospheres that did form was enhanced. Mechanistically, nestin KD-dependent melanoma invasion was associated with intracellular redistribution of phosphorylated focal adhesion kinase and increased melanoma cell responsiveness to transforming growth factor-beta, both implicated in pathways of melanoma invasion. The results suggest that the heretofore poorly understood intermediate filament, nestin, may serve as a novel mediator of MMPs critical to melanoma virulence.
Dolutegravir (DTG) is a first-line antiretroviral drug (ARV) used in combination therapy for the treatment of human immunodeficiency virus type-1 (HIV-1) infection. The drug is effective, safe, and well tolerated. Nonetheless, concerns have recently emerged for its usage in pregnant women or those of child-bearing age. Notably, DTG-based ARV regimens have been linked to birth defects seen as a consequence of periconceptional usages. To this end, uncovering an underlying mechanism for DTG-associated adverse fetal development outcomes has gained clinical and basic research interest. We now report that DTG inhibits matrix metalloproteinases (MMPs) activities that could affect fetal neurodevelopment. DTG is a broad-spectrum MMPs inhibitor and binds to Zn++ at the enzyme's catalytic domain. Studies performed in pregnant mice show that DTG readily reaches the fetal central nervous system during gestation and inhibits MMP activity. Postnatal screenings of brain health in mice pups identified neuroinflammation and neuronal impairment. These abnormalities persist as a consequence of in utero DTG exposure. We conclude that DTG inhibition of MMPs activities during gestation has the potential to affect prenatal and postnatal neurodevelopment.
Nephropathy is serious complication of diabetes. We have previously shown that level of the proteoglycan syndecan-1 in blood is associated with ultrastructural kidney changes in young persons with type 1 diabetes. Dysregulation of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) may contribute to the development of nephropathy. The aim of this study was to investigate if the levels of MMPs in blood samples are potential markers of early nephropathy in type 1 diabetes.
Relapse to cocaine use necessitates remodeling excitatory synapses in the nucleus accumbens and synaptic reorganization requires matrix metalloproteinase (MMP) degradation of the extracellular matrix proteins. We found enduring increases in MMP-2 activity in rats after withdrawal from self-administered cocaine and transient increases in MMP-9 during cue-induced cocaine relapse. Cue-induced heroin and nicotine relapse increased MMP activity, and increased MMP activity was required for both cocaine relapse and relapse-associated synaptic plasticity.
Matrix metalloproteinases (MMPs), a family of endopeptidases also known as gelatinases, have been reported to affect the acquisition of the cell proliferative, cell invasive and metastatic phenotype of several types of cancer. In particular, the gelatinases MMP-2 and -9 have been revealed to facilitate tumor growth and invasion in patients with colorectal cancer (CRC). However, it is not known whether the gelatinase activity of MMP-2 and -9 is also elevated in Vietnamese patients with CRC. The activity of MMP-2 and -9 in the tissue samples of 103 patients with CRC was evaluated by gelatin zymography and quantified using ImageJ. The association between the level of activity of MMP-2 and -9 and various clinicopathological factors was analyzed, and Chisio BioPAX Editor software was used to visualize the biological pathways regulating the activity of the MMPs. The present study noticed significantly increased activity of active MMP-2 and MMP-9 in tumor tissues (P<0.01), and significantly decreased levels of pro-form MMP-2 and MMP-9 in tumor tissues (P<0.01), compared with that in adjacent tissues in patients with CRC. A correlation between the normalized different activity of MMP-2 and -9 and various clinicopathological features was observed. Furthermore, bioinformatics analysis indicated that the alteration in the activity of MMP-2 and MMP-9 may have been controlled by biological pathways involving the tissue inhibitors of metalloprotease-2 and -1. These findings indicate that the activity of the gelatinases MMP-2 and -9 affects the tumor progression and metastasis of patients with CRC, providing a potential novel approach for determining the prognosis of CRC.
Matrix metalloproteinases (MMPs) are identified as modulators of the extracellular matrix in heart failure progression. However, evidence for intracellular effects of MMPs is emerging. Pro- and anti-hypertrophic cardiac effects are described. This may be due to the various sources of different MMPs in the heart tissue. Therefore, the aim of the present study was to determine the role of MMPs in hypertrophic growth of isolated rat ventricular cardiac myocytes.
Cyclic changes, such as growth, decidualization, shedding, and regeneration, in the human endometrium are regulated by the reciprocal action of female hormones, such as estradiol (E2), and progesterone (P4). Matrix metalloproteases (MMPs) and tissue inhibitors of MMPs (TIMPs) control the invasion of extravillous trophoblast cells after implantation. Several MMPs and TIMPs function in the decidua and endometrial stromal cells (ESCs). Here, we aimed to systematically investigate the changes in MMPs and TIMPs associated with ESC decidualization. We evaluated the expression of 23 MMPs, four TIMPs, and four anti-sense non-coding RNAs from MMP loci. Primary ESC cultures treated with E2 + medroxyprogesterone acetate (MPA), a potent P4 receptor agonist, showed significant down-regulation of MMP3, MMP10, MMP11, MMP12, MMP20, and MMP27 in decidualized ESCs, as assessed by quantitative reverse transcription PCR. Further, MMP15 and MMP19 were significantly upregulated in decidualized ESCs. siRNA-mediated silencing of Heart and Neural Crest Derivatives Expressed 2 (HAND2), a master transcriptional regulator in ESC decidualization, significantly increased MMP15 expression in untreated human ESCs. These results collectively indicate the importance of MMP15 and MMP19 in ESC decidualization and highlight the role of HAND2 in repressing MMP15 transcription, thereby regulating decidualization.
Matrix metalloproteinases (MMPs) play an important role in bone resorption and are regulated by tissue inhibitors of metalloproteinases (TIMPs). We investigated the use of MMP2/TIMP2 and MMP9/TIMP1 ratios as biomarkers of bone resorption in geriatric osteoporosis and evaluated the relationship between osteoporosis and geriatric syndromes.
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