Editorial

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Open AccessEditorial

Matrix Metalloproteinases in Health and Disease

by Raffaele Serra

Biomolecules 2020, 10(8), 1138; https://doi.org/10.3390/biom10081138 - 01 Aug 2020

Cited by 18 | Viewed by 2093

Matrix metalloproteinases (MMPs) are members of an enzyme family and, under normal physiological conditions, are critical for maintaining tissue allostasis [...] Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease)

Research

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13 pages, 3096 KiB

Open AccessArticle

Novel Barbiturate-Nitrate Compounds Inhibit the Upregulation of Matrix Metalloproteinase-9 Gene Expression in Intestinal Inflammation through a cGMP-Mediated Pathway

by Shane O’Sullivan, Jun Wang, Marek W. Radomski, John F. Gilmer and Carlos Medina

Biomolecules 2020, 10(5), 808; https://doi.org/10.3390/biom10050808 - 25 May 2020

Cited by 6 | Viewed by 2508

Abstract

Matrix metalloproteinase-9 is upregulated in inflammatory bowel disease. Barbiturate nitrate hybrid compounds have been designed to inhibit MMP secretion and enzyme activity. In this study, we investigated the mechanism of action of barbiturate-nitrate hybrid compounds and their component parts using models of intestinal [...] Read more.

Matrix metalloproteinase-9 is upregulated in inflammatory bowel disease. Barbiturate nitrate hybrid compounds have been designed to inhibit MMP secretion and enzyme activity. In this study, we investigated the mechanism of action of barbiturate-nitrate hybrid compounds and their component parts using models of intestinal inflammation in vitro. Cytokine-stimulated Caco-2 cells were used in all in vitro experiments. The NO donors SNAP and DETA-NONOate were used to study the effect of NO on MMP-9 mRNA. Mechanistic elucidation was carried out using the soluble guanylate cyclase (sGC) inhibitor, ODQ, and the cGMP analogue, 8-Bromo-cGMP. Further experiments were carried out to elucidate the role of NF-κB. NO donors exerted an inhibitory effect on MMP-9 mRNA in cytokine-stimulated cells. While the non-nitrate barbiturates had a limited effect on MMP-9 expression, the hybrid compounds inhibited MMP-9 expression through its NO-mimetic properties. No effect could be observed on mRNA for MMP-1 or MMP-2. The sGC inhibitior, ODQ, abolished the nitrate-barbiturate inhibition of MMP-9 gene expression, an effect which was reversed by 8-Br-cGMP. This study shows that the barbiturate scaffold is suitable for hybrid design as an MMP-9 inhibitor in cytokine-stimulated Caco-2 cells. The inhibition of MMP-9 levels was largely mediated through a reduction in its mRNA by a sGC/cGMP pathway mediated mechanism. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease)

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11 pages, 2381 KiB

Open AccessArticle

Transient Expression of Reck Under Hepatic Ischemia/Reperfusion Conditions Is Associated with Mapk Signaling Pathways

by Andrea Ferrigno, Laura G. Di Pasqua, Giuseppina Palladini, Clarissa Berardo, Roberta Verta, Plinio Richelmi, Stefano Perlini, Debora Collotta, Massimo Collino and Mariapia Vairetti

Biomolecules 2020, 10(5), 747; https://doi.org/10.3390/biom10050747 - 11 May 2020

Cited by 9 | Viewed by 2060

Abstract

In this study, we demonstrated the involvement of matrix metalloproteinases (MMPs) in hepatic ischemia/reperfusion (I/R) injury. Our aim is to evaluate the impact of reperfusion on I/R-related changes in RECK, an MMP modulator, and mitogen-activated protein kinase (MAPKs) pathways (ERK, p38, and JNK). [...] Read more.

In this study, we demonstrated the involvement of matrix metalloproteinases (MMPs) in hepatic ischemia/reperfusion (I/R) injury. Our aim is to evaluate the impact of reperfusion on I/R-related changes in RECK, an MMP modulator, and mitogen-activated protein kinase (MAPKs) pathways (ERK, p38, and JNK). Male Wistar rats were either subjected to 60 min partial-hepatic ischemia or sham-operated. After a 60 min or 120 min reperfusion, liver samples were collected for analysis of MMP-2 and MMP-9 by zymography and RECK, TIMP-1, and TIMP-2 content, MAPKs activation (ERK1/2, JNK1/2, and p38), as well as iNOS and eNOS by Western blot. Serum enzymes AST, ALT, and alkaline-phosphatase were quantified. A transitory decrease in hepatic RECK and TIMPs was associated with a transitory increase in both MMP-2 and MMP-9 activity and a robust activation of ERK1/2, JNK1/2, and p38 were detected at 60 min reperfusion. Hepatic expression of iNOS was maximally upregulated at 120 min reperfusion. An increase in eNOS was detected at 120 min reperfusion. I/R evoked significant hepatic injury in a time-dependent manner. These findings provide new insights into the underlying molecular mechanisms of reperfusion in inducing hepatic injury: a transitory decrease in RECK and TIMPs and increases in both MAPK and MMP activity suggest their role as triggering factors of the organ dysfunction. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease)

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9 pages, 1683 KiB

Open AccessArticle

CD147 is a Novel Interaction Partner of Integrin αMβ2 Mediating Leukocyte and Platelet Adhesion

by David Heinzmann, Moritz Noethel, Saskia von Ungern-Sternberg, Ioannis Mitroulis, Meinrad Gawaz, Triantafyllos Chavakis, Andreas E. May and Peter Seizer

Biomolecules 2020, 10(4), 541; https://doi.org/10.3390/biom10040541 - 02 Apr 2020

Cited by 14 | Viewed by 3266

Abstract

Surface receptor-mediated adhesion is a fundamental step in the recruitment of leukocytes and platelets, as well as platelet–leukocyte interactions. The surface receptor CD147 is crucially involved in host defense against self-derived and invading targets, as well as in thrombosis. In the current study, [...] Read more.

Surface receptor-mediated adhesion is a fundamental step in the recruitment of leukocytes and platelets, as well as platelet–leukocyte interactions. The surface receptor CD147 is crucially involved in host defense against self-derived and invading targets, as well as in thrombosis. In the current study, we describe the previously unknown interaction of CD147 with integrin αMβ2 (Mac-1) in this context. Using binding assays, we were able to show a stable interaction of CD147 with Mac-1 in vitro. Leukocytes from Mac-1^−/− and CD147^+/− mice showed a markedly reduced static adhesion to CD147- and Mac-1-coated surfaces, respectively, compared to wild-type mice. Similarly, we observed reduced rolling and adhesion of monocytes under flow conditions when cells were pre-treated with antibodies against Mac-1 or CD147. Additionally, as assessed by antibody inhibition experiments, CD147 mediated the dynamic adhesion of platelets to Mac-1-coated surfaces. The interaction of CD147 with Mac-1 is a previously undescribed mechanism facilitating the adhesion of leukocytes and platelets. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease)

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13 pages, 1743 KiB

Open AccessArticle

Variations in Circulating Active MMP-9 Levels during Renal Replacement Therapy

by Elena Rodríguez-Sánchez, José Alberto Navarro-García, Jennifer Aceves-Ripoll, Judith Abarca-Zabalía, Andrea Susmozas-Sánchez, Teresa Bada-Bosch, Eduardo Hernández, Evangelina Mérida-Herrero, Amado Andrés, Manuel Praga, Mario Fernández-Ruiz, José María Aguado, Julián Segura, Luis Miguel Ruilope and Gema Ruiz-Hurtado

Biomolecules 2020, 10(4), 505; https://doi.org/10.3390/biom10040505 - 26 Mar 2020

Cited by 4 | Viewed by 2130

Abstract

Renal replacement therapy (RRT) is complicated by a chronic state of inflammation and a high mortality risk. However, different RRT modalities can have a selective impact on markers of inflammation and oxidative stress. We evaluated the levels of active matrix metalloproteinase (MMP)-9 in [...] Read more.

Renal replacement therapy (RRT) is complicated by a chronic state of inflammation and a high mortality risk. However, different RRT modalities can have a selective impact on markers of inflammation and oxidative stress. We evaluated the levels of active matrix metalloproteinase (MMP)-9 in patients undergoing two types of dialysis (high-flux dialysis (HFD) and on-line hemodiafiltration (OL-HDF)) and in kidney transplantation (KT) recipients. Active MMP-9 was measured by zymography and ELISA before (pre-) and after (post-) one dialysis session, and at baseline and follow-up (7 and 14 days, and 1, 3, 6, and 12 months) after KT. Active MMP-9 decreased post-dialysis only in HFD patients, while the levels in OL-HDF patients were already lower before dialysis. Active MMP-9 increased at 7 and 14 days post-KT and was restored to baseline levels three months post-KT, coinciding with an improvement in renal function and plasma creatinine. Active MMP-9 correlated with pulse pressure as an indicator of arterial stiffness both in dialysis patients and KT recipients. In conclusion, active MMP-9 is better controlled in OL-HDF than in HFD and is restored to baseline levels along with stabilization of renal parameters after KT. Active MMP-9 might act as a biomarker of arterial stiffness in RRT. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease)

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11 pages, 585 KiB

Open AccessArticle

An Oral Rinse Active Matrix Metalloproteinase-8 Point-of-Care Immunotest May Be Less Accurate in Patients with Crohn’s Disease

by Jaana Rautava, Ulvi K. Gürsoy, Adrian Kullström, Eija Könönen, Timo Sorsa, Taina Tervahartiala and Mervi Gürsoy

Biomolecules 2020, 10(3), 395; https://doi.org/10.3390/biom10030395 - 04 Mar 2020

Cited by 20 | Viewed by 2297

Abstract

The diagnostic accuracy of point-of-care (PoC) applications may be compromised in individuals with additional inflammatory conditions. This cross-sectional study examined the performance of a commercial oral rinse active matrix metalloproteinase-8 (aMMP-8) PoC immunotest in individuals with (n = 47) and without Crohn’s [...] Read more.

The diagnostic accuracy of point-of-care (PoC) applications may be compromised in individuals with additional inflammatory conditions. This cross-sectional study examined the performance of a commercial oral rinse active matrix metalloproteinase-8 (aMMP-8) PoC immunotest in individuals with (n = 47) and without Crohn’s disease (CD) (n = 41). Oral rinse collected from the participants was analyzed by the PoC immunotest. Molecular forms and fragments of salivary MMP-8 were detected by western immunoblotting. The sensitivity of the immunotest for periodontitis was 60.0% in the CD group and 90.0% in the control group. The respective specificity was 75.0% and 80.0%. In both groups, clinical diagnosis of periodontitis exhibited a significant association with the immunotest results, however, the odds ratio (OR) was more than ten-fold in controls (OR 54.3, 95% CI: 3.1–953, p = 0.006) in comparison to CD patients (OR 5.2, 95% CI: 1.3–21.6, p = 0.022). According to Western immunoblot results, the immunotest MMP-8 positivity was not related to elevated levels of molecular forms and fragments of MMP-8 in the CD group, as in the control group. The diagnostic accuracy of the aMMP-8 PoC oral rinse immunotest is reduced in CD patients, which may be related to lower levels or undetectable complexes. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease)

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11 pages, 1140 KiB

Open AccessArticle

Expression of MMP-2, MMP-9, and NGAL in Tissue and Serum of Patients with Vascular Aneurysms and Their Modulation by Statin Treatment: A Pilot Study

by Erika Cione, Elena Piegari, Giuseppe Gallelli, Maria Cristina Caroleo, Elena Lamirata, Francesca Curcio, Federica Colosimo, Roberto Cannataro, Nicola Ielapi, Manuela Colosimo, Stefano de Franciscis and Luca Gallelli

Biomolecules 2020, 10(3), 359; https://doi.org/10.3390/biom10030359 - 26 Feb 2020

Cited by 14 | Viewed by 2811

Abstract

Background: Matrix metalloproteinases (MMPs) are involved in vascular wall degradation, and drugs able to modulate MMP activity can be used to prevent or treat aneurysmal disease. In this study, we evaluated the effects of statins on MMP-2, MMP-9, and neutrophil gelatinase-associated lipocalin (NGAL) [...] Read more.

Background: Matrix metalloproteinases (MMPs) are involved in vascular wall degradation, and drugs able to modulate MMP activity can be used to prevent or treat aneurysmal disease. In this study, we evaluated the effects of statins on MMP-2, MMP-9, and neutrophil gelatinase-associated lipocalin (NGAL) in both plasma and tissue in patients with aneurysmal disease. Methods: We performed a prospective, single-blind, multicenter, control group clinical drug trial on 184 patients of both sexes >18 years old with a diagnosis of arterial aneurysmal disease. Enrolled patients were divided into two groups: Group I under statin treatment and Group II not taking statins. In addition, 122 patients without aneurysmal disease and under statin treatment were enrolled as a control group (Group III). The expression of MMPs and NGAL in plasma was evaluated using ELISA, while their expression in endothelial tissues was evaluated using Western blot. Results: The ELISA test revealed greater plasma levels (p < 0.01) of MMPs and NGAL in Groups I and II vs. Group III. Western blot analysis showed higher expression (p < 0.01) of MMPs and NGAL in Group II vs. Group I, and this increase was significantly higher (p < 0.01) in patients treated with low potency statins compared to high potency ones. Conclusions: MMPs and NGAL seem to play a major role in the development of aneurysms, and their modulation by statins suggests that these drugs could be used to prevent arterial aneurysmal disease. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease)

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11 pages, 477 KiB

Open AccessArticle

MMP2 Polymorphism Affects Plasma Matrix Metalloproteinase (MMP)-2 Levels, and Correlates with the Decline in Lung Function in Hypersensitivity Pneumonitis Positive to Autoantibodies Patients

by Luis Santiago-Ruiz, Ivette Buendía-Roldán, Gloria Pérez-Rubio, Enrique Ambrocio-Ortiz, Mayra Mejía, Martha Montaño and Ramcés Falfán-Valencia

Biomolecules 2019, 9(10), 574; https://doi.org/10.3390/biom9100574 - 05 Oct 2019

Cited by 5 | Viewed by 3727

Abstract

Among hypersensitivity pneumonitis (HP) patients have been identified who develop autoantibodies with and without clinical manifestations of autoimmune disease. Genetic factors involved in this process and the effect of these autoantibodies on the clinical phenotype are unknown. Matrix metalloproteinases (MMPs) have an important [...] Read more.

Among hypersensitivity pneumonitis (HP) patients have been identified who develop autoantibodies with and without clinical manifestations of autoimmune disease. Genetic factors involved in this process and the effect of these autoantibodies on the clinical phenotype are unknown. Matrix metalloproteinases (MMPs) have an important role in architecture and pulmonary remodeling. The aim of our study was to identify polymorphisms in the MMP1, MMP2, MMP9 and MMP12 genes associated with susceptibility to HP with the presence of autoantibodies (HPAbs+). Using the dominant model of genetic association, comparisons were made between three groups. For rs7125062 in MMP1 (CC vs. CT+TT), we found an association when comparing groups of patients with healthy controls: HPAbs+ vs. HC (p < 0.001, OR = 10.62, CI 95% = 4.34–25.96); HP vs. HC (p < 0.001, OR = 7.85, 95% CI 95% = 4.54–13.57). This rs11646643 in MMP2 shows a difference in the HPAbs+ group by the dominant genetic model GG vs. GA+AA, (p = 0.001, OR = 8.11, CI 95% = 1.83–35.84). In the linear regression analysis, rs11646643 was associated with a difference in basal forced vital capacity (FVC)/12 months (p = 0.013, β = 0.228, 95% CI95% = 1.97–16.72). We identified single-nucleotide polymorphisms (SNPs) associated with the risk of developing HP, and with the evolution towards the phenotype with the presence of autoantibodies. Also, to the decrease in plasma MMP-2 levels. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease)

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Review

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Open AccessReview

The Many Faces of Matrix Metalloproteinase-7 in Kidney Diseases

by Zhao Liu, Roderick J. Tan and Youhua Liu

Biomolecules 2020, 10(6), 960; https://doi.org/10.3390/biom10060960 - 25 Jun 2020

Cited by 51 | Viewed by 4928

Abstract

Matrix metalloproteinase-7 (MMP-7) is a secreted zinc-dependent endopeptidase that is implicated in regulating kidney homeostasis and diseases. MMP-7 is produced as an inactive zymogen, and proteolytic cleavage is required for its activation. MMP-7 is barely expressed in normal adult kidney but upregulated in [...] Read more.

Matrix metalloproteinase-7 (MMP-7) is a secreted zinc-dependent endopeptidase that is implicated in regulating kidney homeostasis and diseases. MMP-7 is produced as an inactive zymogen, and proteolytic cleavage is required for its activation. MMP-7 is barely expressed in normal adult kidney but upregulated in acute kidney injury (AKI) and chronic kidney disease (CKD). The expression of MMP-7 is transcriptionally regulated by Wnt/β-catenin and other cues. As a secreted protein, MMP-7 is present and increased in the urine of patients, and its levels serve as a noninvasive biomarker for predicting AKI prognosis and monitoring CKD progression. Apart from degrading components of the extracellular matrix, MMP-7 also cleaves a wide range of substrates, such as E-cadherin, Fas ligand, and nephrin. As such, it plays an essential role in regulating many cellular processes, such as cell proliferation, apoptosis, epithelial-mesenchymal transition, and podocyte injury. The function of MMP-7 in kidney diseases is complex and context-dependent. It protects against AKI by priming tubular cells for survival and regeneration but promotes kidney fibrosis and CKD progression. MMP-7 also impairs podocyte integrity and induces proteinuria. In this review, we summarized recent advances in our understanding of the regulation, role, and mechanisms of MMP-7 in the pathogenesis of kidney diseases. We also discussed the potential of MMP-7 as a biomarker and therapeutic target in a clinical setting. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease)

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61 pages, 55247 KiB

Open AccessReview

Challenges in Matrix Metalloproteinases Inhibition

by Helena Laronha, Inês Carpinteiro, Jaime Portugal, Ana Azul, Mário Polido, Krasimira T. Petrova, Madalena Salema-Oom and Jorge Caldeira

Biomolecules 2020, 10(5), 717; https://doi.org/10.3390/biom10050717 - 05 May 2020

Cited by 41 | Viewed by 4645

Abstract

Matrix metalloproteinases are enzymes that degrade the extracellular matrix. They have different substrates but similar structural organization. Matrix metalloproteinases are involved in many physiological and pathological processes and there is a need to develop inhibitors for these enzymes in order to modulate the [...] Read more.

Matrix metalloproteinases are enzymes that degrade the extracellular matrix. They have different substrates but similar structural organization. Matrix metalloproteinases are involved in many physiological and pathological processes and there is a need to develop inhibitors for these enzymes in order to modulate the degradation of the extracellular matrix (ECM). There exist two classes of inhibitors: endogenous and synthetics. The development of synthetic inhibitors remains a great challenge due to the low selectivity and specificity, side effects in clinical trials, and instability. An extensive review of currently reported synthetic inhibitors and description of their properties is presented. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease)

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16 pages, 1023 KiB

Open AccessReview

The Association of Matrix Metalloproteinases with Chronic Kidney Disease and Peripheral Vascular Disease: A Light at the End of the Tunnel?

by Michele Provenzano, Michele Andreucci, Carlo Garofalo, Teresa Faga, Ashour Michael, Nicola Ielapi, Raffaele Grande, Paolo Sapienza, Stefano de Franciscis, Pasquale Mastroroberto and Raffaele Serra

Biomolecules 2020, 10(1), 154; https://doi.org/10.3390/biom10010154 - 17 Jan 2020

Cited by 57 | Viewed by 4323

Abstract

Chronic Kidney Disease (CKD) represents a risk factor for fatal and nonfatal cardiovascular (CV) events, including peripheral vascular disease (PVD). This occurs because CKD encompasses several factors that lead to poor prognoses, mainly due to a reduction of the estimated glomerular filtration rate [...] Read more.

Chronic Kidney Disease (CKD) represents a risk factor for fatal and nonfatal cardiovascular (CV) events, including peripheral vascular disease (PVD). This occurs because CKD encompasses several factors that lead to poor prognoses, mainly due to a reduction of the estimated glomerular filtration rate (eGFR), the presence of proteinuria, and the uremic inflammatory milieu. The matrix metalloproteinases (MMPs) are a group of zinc-containing endopeptidases implicated in extracellular matrix (ECM) remodeling, a systemic process in tissue homeostasis. MMPs play an important role in cell differentiation, angiogenesis, inflammation, and vascular damage. Our aim was to review the published evidence regarding the association between MMPs, PVD, and CKD to find possible common pathophysiological mechanisms. MMPs favor ECM deposition through the glomeruli, and start the shedding of cellular junctions and epithelial-mesenchymal transition in the renal tubules. MMP-2 and -9 have also been associated with the presence of systemic vascular damage, since they exert a pro-inflammatory and proatherosclerotic actions. An imbalance of MMPs was found in the context of PVD, where MMPs are predictors of poor prognoses in patients who underwent lower extremity revascularization. MMP circulating levels are increased in both conditions, i.e., that of CKD and PVD. A possible pathogenic link between these conditions is represented by the enhanced production of transforming growth factor-β that worsens vascular calcifications and atherosclerosis and the development of proteinuria in patients with increased levels of MMPs. Proteinuria has been recognized as a marker of systemic vascular damage, and this may explain in part the increase in CV risk that is manifest in patients with CKD and PVD. In conclusion, MMPs can be considered a useful tool by which to stratify CV risk in patients with CKD and PVD. Further studies are needed to investigate the causal-relationships between MMPs, CKD, and PVD, and to optimize their prognostic and predictive (in response to treatments) roles. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease)

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