Biomolecules

Research

18 pages, 2809 KiB

Open AccessEditor’s ChoiceArticle

Tissue Inhibitor of Matrix Metalloproteinases-1 (TIMP-1) and Pulmonary Involvement in COVID-19 Pneumonia

by Maria Antonella Zingaropoli, Tiziana Latronico, Patrizia Pasculli, Giorgio Maria Masci, Roberta Merz, Federica Ciccone, Federica Dominelli, Cosmo Del Borgo, Miriam Lichtner, Franco Iafrate, Gioacchino Galardo, Francesco Pugliese, Valeria Panebianco, Paolo Ricci, Carlo Catalano, Maria Rosa Ciardi, Grazia Maria Liuzzi and Claudio Maria Mastroianni

Biomolecules 2023, 13(7), 1040; https://doi.org/10.3390/biom13071040 - 26 Jun 2023

Cited by 3 | Viewed by 1285

Abstract

Background: The aim of the study was to longitudinally evaluate the association between MMP-2, MMP-9, TIMP-1 and chest radiological findings in COVID-19 patients. Methods: COVID-19 patients were evaluated based on their hospital admission (baseline) and three months after hospital discharge (T post) and [...] Read more.

Background: The aim of the study was to longitudinally evaluate the association between MMP-2, MMP-9, TIMP-1 and chest radiological findings in COVID-19 patients. Methods: COVID-19 patients were evaluated based on their hospital admission (baseline) and three months after hospital discharge (T post) and were stratified into ARDS and non-ARDS groups. As a control group, healthy donors (HD) were enrolled. Results: At the baseline, compared to HD (n = 53), COVID-19 patients (n = 129) showed higher plasma levels of MMP-9 (p < 0.0001) and TIMP-1 (p < 0.0001) and the higher plasma activity of MMP-2 (p < 0.0001) and MMP-9 (p < 0.0001). In the ARDS group, higher plasma levels of MMP-9 (p = 0.0339) and TIMP-1 (p = 0.0044) and the plasma activity of MMP-2 (p = 0.0258) and MMP-9 (p = 0.0021) compared to non-ARDS was observed. A positive correlation between the plasma levels of TIMP-1 and chest computed tomography (CT) score (ρ = 0.2302, p = 0.0160) was observed. At the T post, a reduction in plasma levels of TIMP-1 (p < 0.0001), whereas an increase in the plasma levels of MMP-9 was observed (p = 0.0088). Conclusions: The positive correlation between TIMP-1 with chest CT scores highlights its potential use as a marker of fibrotic burden. At T post, the increase in plasma levels of MMP-9 and the reduction in plasma levels of TIMP-1 suggested that inflammation and fibrosis resolution were still ongoing. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 3.0)

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21 pages, 8423 KiB

Open AccessArticle

Matrix Metalloproteinases Contribute to the Calcification Phenotype in Pseudoxanthoma Elasticum

by Ricarda Plümers, Christopher Lindenkamp, Michel Robin Osterhage, Cornelius Knabbe and Doris Hendig

Biomolecules 2023, 13(4), 672; https://doi.org/10.3390/biom13040672 - 12 Apr 2023

Viewed by 1457

Abstract

Ectopic calcification and dysregulated extracellular matrix remodeling are prominent hallmarks of the complex heterogenous pathobiochemistry of pseudoxanthoma elasticum (PXE). The disease arises from mutations in ABCC6, an ATP-binding cassette transporter expressed predominantly in the liver. Neither its substrate nor the mechanisms by [...] Read more.

Ectopic calcification and dysregulated extracellular matrix remodeling are prominent hallmarks of the complex heterogenous pathobiochemistry of pseudoxanthoma elasticum (PXE). The disease arises from mutations in ABCC6, an ATP-binding cassette transporter expressed predominantly in the liver. Neither its substrate nor the mechanisms by which it contributes to PXE are completely understood. The fibroblasts isolated from PXE patients and Abcc6^−/− mice were subjected to RNA sequencing. A group of matrix metalloproteinases (MMPs) clustering on human chromosome 11q21-23, respectively, murine chromosome 9, was found to be overexpressed. A real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescent staining confirmed these findings. The induction of calcification by CaCl₂ resulted in the elevated expression of selected MMPs. On this basis, the influence of the MMP inhibitor Marimastat (BB-2516) on calcification was assessed. PXE fibroblasts (PXEFs) exhibited a pro-calcification phenotype basally. PXEF and normal human dermal fibroblasts responded with calcium deposit accumulation and the induced expression of osteopontin to the addition of Marimastat to the calcifying medium. The raised MMP expression in PXEFs and during cultivation with calcium indicates a correlation of ECM remodeling and ectopic calcification in PXE pathobiochemistry. We assume that MMPs make elastic fibers accessible to controlled, potentially osteopontin-dependent calcium deposition under calcifying conditions. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 3.0)

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13 pages, 2549 KiB

Open AccessArticle

The Protective Effect of Simvastatin on the Systolic Function of the Heart in the Model of Acute Ischemia and Reperfusion Is Due to Inhibition of the RhoA Pathway and Independent of Reduction of MMP-2 Activity

by Monika Skrzypiec-Spring, Agnieszka Sapa-Wojciechowska, Alina Rak-Pasikowska, Maciej Kaczorowski, Iwona Bil-Lula, Agnieszka Hałoń and Adam Szeląg

Biomolecules 2022, 12(9), 1291; https://doi.org/10.3390/biom12091291 - 13 Sep 2022

Cited by 3 | Viewed by 1712

Abstract

The present study investigated whether Rho-associated protein kinase (RhoA/ROCK) signaling pathway inhibitor simvastatin inhibits matrix metalloproteinase 2 (MMP-2) activity in a rat ischemia-reperfusion injury (I/Ri) model by inhibiting the RhoA/ROCK pathway and reducing MMP-2 mRNA levels. Isolated rat hearts were subjected to aerobic [...] Read more.

The present study investigated whether Rho-associated protein kinase (RhoA/ROCK) signaling pathway inhibitor simvastatin inhibits matrix metalloproteinase 2 (MMP-2) activity in a rat ischemia-reperfusion injury (I/Ri) model by inhibiting the RhoA/ROCK pathway and reducing MMP-2 mRNA levels. Isolated rat hearts were subjected to aerobic perfusion or I/Ri control. The effect of simvastatin was assessed in hearts subjected to I/Ri. We determined cardiac mechanical function, the content of RhoA, phosphorylated myosin light chain subunit 1 (phospho-MYL9), troponin I, MMP-2, and MMP-2 mRNA in the heart homogenates, as well as MMP-2 activity in heart tissue. We showed that treatment with simvastatin caused improvement in the contractile function of the heart subjected to I/Ri which was accompanied by a decrease of MMP-2 activity in heart tissue along with inhibition of RhoA pathway, expressed in a reduction in both RhoA and its downstream product—phosphorylated myosin light chain (phospho-MYL9) in hearts treated with simvastatin. MMP-2 inactivation is not due to inhibition of MMP-2 m-RNA synthesis caused by inhibition of RhoA/ROCK pathway and is due, at least in part, to the direct drug action. The protective effect of simvastatin on systolic function in the acute ischemia-reperfusion model does not appear to be related to reduced MMP-2 activation, but other mechanisms related with the inhibition RhoA/ROCK pathway. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 3.0)

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Review

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12 pages, 1636 KiB

Open AccessReview

The Role of MMPs in the Era of CFTR Modulators: An Additional Target for Cystic Fibrosis Patients?

by Renata Esposito, Davida Mirra, Giuseppe Spaziano, Francesca Panico, Luca Gallelli and Bruno D’Agostino

Biomolecules 2023, 13(2), 350; https://doi.org/10.3390/biom13020350 - 10 Feb 2023

Cited by 3 | Viewed by 1564

Abstract

Cystic fibrosis (CF) is a high-prevalence disease characterized by significant lung remodeling, responsible for high morbidity and mortality worldwide. The lung structural changes are partly due to proteolytic activity associated with inflammatory cells such as neutrophils and macrophages. Matrix metalloproteases (MMPs) are the [...] Read more.

Cystic fibrosis (CF) is a high-prevalence disease characterized by significant lung remodeling, responsible for high morbidity and mortality worldwide. The lung structural changes are partly due to proteolytic activity associated with inflammatory cells such as neutrophils and macrophages. Matrix metalloproteases (MMPs) are the major proteases involved in CF, and recent literature data focused on their potential role in the pathogenesis of the disease. In fact, an imbalance of proteases and antiproteases was observed in CF patients, resulting in dysfunction of protease activity and loss of lung homeostasis. Currently, many steps forward have been moved in the field of pharmacological treatment with the recent introduction of triple-combination therapy targeting the CFTR channel. Despite CFTR modulator therapy potentially being effective in up to 90% of patients with CF, there are still patients who are not eligible for the available therapies. Here, we introduce experimental drugs to provide updates on therapy evolution regarding a proportion of CF non-responder patients to current treatment, and we summarize the role of MMPs in pathogenesis and as future therapeutic targets of CF. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 3.0)

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22 pages, 3586 KiB

Open AccessReview

Metalloproteases in Pain Generation and Persistence: A Possible Target?

by Gianmarco Marcianò, Cristina Vocca, Vincenzo Rania, Rita Citraro, Giovambattista De Sarro and Luca Gallelli

Biomolecules 2023, 13(2), 268; https://doi.org/10.3390/biom13020268 - 31 Jan 2023

Cited by 4 | Viewed by 1685

Abstract

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent proteolytic enzymes associated with extracellular matrix protein turnover and tissue degradation. They participate to many different physiological reactions but are also hyperactivated in several diseases. Various literature studies have documented that MMPs play a [...] Read more.

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent proteolytic enzymes associated with extracellular matrix protein turnover and tissue degradation. They participate to many different physiological reactions but are also hyperactivated in several diseases. Various literature studies have documented that MMPs play a role in the modulation of neuropathic and nociceptive pain. The heterogeneity of clinical and pre-clinical data is an important issue in this experimental context. Despite the presence of a good number of studies on MMP inhibitors, these drugs showed scarce efficacy and relevant side effects. In the present manuscript, we reviewed studies in the literature that define a possible role of MMPs in pain and the effects of their modulation. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 3.0)

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22 pages, 1761 KiB

Open AccessReview

Matrix Metalloproteinases and Glaucoma

by Moo Hyun Kim and Su-Ho Lim

Biomolecules 2022, 12(10), 1368; https://doi.org/10.3390/biom12101368 - 25 Sep 2022

Cited by 7 | Viewed by 3675

Abstract

Matrix metalloproteinases (MMPs) are enzymes that decompose extracellular matrix (ECM) proteins. MMPs are thought to play important roles in cellular processes, such as cell proliferation, differentiation, angiogenesis, migration, apoptosis, and host defense. MMPs are distributed in almost all intraocular tissues and are involved [...] Read more.

Matrix metalloproteinases (MMPs) are enzymes that decompose extracellular matrix (ECM) proteins. MMPs are thought to play important roles in cellular processes, such as cell proliferation, differentiation, angiogenesis, migration, apoptosis, and host defense. MMPs are distributed in almost all intraocular tissues and are involved in physiological and pathological mechanisms of the eye. MMPs are also associated with glaucoma, a progressive neurodegenerative disease of the eyes. MMP activity affects intraocular pressure control and apoptosis of retinal ganglion cells, which are the pathological mechanisms of glaucoma. It also affects the risk of glaucoma development based on genetic pleomorphism. In addition, MMPs may affect the treatment outcomes of glaucoma, including the success rate of surgical treatment and side effects on the ocular surface due to glaucoma medications. This review discusses the various relationships between MMP and glaucoma. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 3.0)

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28 pages, 1240 KiB

Open AccessFeature PaperReview

The Mechanism and Role of ADAMTS Protein Family in Osteoarthritis

by Ting Li, Jie Peng, Qingqing Li, Yuan Shu, Peijun Zhu and Liang Hao

Biomolecules 2022, 12(7), 959; https://doi.org/10.3390/biom12070959 - 08 Jul 2022

Cited by 26 | Viewed by 4949

Abstract

Osteoarthritis (OA) is a principal cause of aches and disability worldwide. It is characterized by the inflammation of the bone leading to degeneration and loss of cartilage function. Factors, including diet, age, and obesity, impact and/or lead to osteoarthritis. In the past few [...] Read more.

Osteoarthritis (OA) is a principal cause of aches and disability worldwide. It is characterized by the inflammation of the bone leading to degeneration and loss of cartilage function. Factors, including diet, age, and obesity, impact and/or lead to osteoarthritis. In the past few years, OA has received considerable scholarly attention owing to its increasing prevalence, resulting in a cumbersome burden. At present, most of the interventions only relieve short-term symptoms, and some treatments and drugs can aggravate the disease in the long run. There is a pressing need to address the safety problems due to osteoarthritis. A disintegrin-like and metalloprotease domain with thrombospondin type 1 repeats (ADAMTS) metalloproteinase is a kind of secretory zinc endopeptidase, comprising 19 kinds of zinc endopeptidases. ADAMTS has been implicated in several human diseases, including OA. For example, aggrecanases, ADAMTS-4 and ADAMTS-5, participate in the cleavage of aggrecan in the extracellular matrix (ECM); ADAMTS-7 and ADAMTS-12 participate in the fission of Cartilage Oligomeric Matrix Protein (COMP) into COMP lyase, and ADAMTS-2, ADAMTS-3, and ADAMTS-14 promote the formation of collagen fibers. In this article, we principally review the role of ADAMTS metalloproteinases in osteoarthritis. From three different dimensions, we explain how ADAMTS participates in all the following aspects of osteoarthritis: ECM, cartilage degeneration, and synovial inflammation. Thus, ADAMTS may be a potential therapeutic target in osteoarthritis, and this article may render a theoretical basis for the study of new therapeutic methods for osteoarthritis. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 3.0)

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Other

Jump to: Research, Review

11 pages, 1118 KiB

Open AccessSystematic Review

A Systematic Review on the Role of Matrix Metalloproteinases in the Pathogenesis of Inguinal Hernias

by Umberto Bracale, Roberto Peltrini, Biancamaria Iacone, Mirko Martirani, Daniele Sannino, Antonio Gargiulo, Francesco Corcione, Raffaele Serra and Umberto Marcello Bracale

Biomolecules 2023, 13(7), 1123; https://doi.org/10.3390/biom13071123 - 14 Jul 2023

Cited by 2 | Viewed by 1153

Abstract

The recurrence rate in patients who undergo surgery for abdominal wall hernias (AWHs) is high. AWHs have been hypothesized to be a disease of the extracellular matrix, which is supported by evidence showing a high incidence of AWHs in patients with connective tissue [...] Read more.

The recurrence rate in patients who undergo surgery for abdominal wall hernias (AWHs) is high. AWHs have been hypothesized to be a disease of the extracellular matrix, which is supported by evidence showing a high incidence of AWHs in patients with connective tissue disorders. This study aimed to investigate the most recent literature studies describing the levels of several matrix metalloproteinases (MMPs) in the blood and fascia, with the objective of better clarifying the pathogenetic role of matrix metalloproteinases (MMPs) and their inhibitors in inguinal hernias (IHs). A systematic literature search was conducted using the PubMed, Scopus, and Web of Science electronic databases to identify eligible studies. The identified studies were included in the analysis, and a qualitative synthesis of the results is provided to describe the most recent findings. Seventeen studies were included. An association between MMP-2 and direct IHs has also been demonstrated. MMP-1, MMP-2, MMP-9, MMP-12, and MMP-13 levels were increased in both the serum and fascia of patients with IHs. The analysis of inhibitors showed an increase in tissue inhibitors of metalloproteinases (TIMPs), specifically TIMP-1 in IHs, particularly in direct hernias, and a reduction in TIMP-2 in the biopsy samples of the transversalis fascia. In contrast, a reduction in TIMP-1 and an increase in TIMP-2 levels have been reported only in the serum of patients with IHs. Metalloproteinases play a crucial role in the pathogenesis of IHs. The analysis of other molecules, such as TIMPs or their correlation with specific genes, is enhancing our understanding of the pathophysiology of IHs. However, more prospective studies, including comprehensive clinical and laboratory data collection, are required to confirm the relationship between the studied biomarkers and the risk of IHs. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 3.0)

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15 pages, 862 KiB

Open AccessSystematic Review

Metalloproteinases and Hypertrophic Cardiomyopathy: A Systematic Review

by Giuseppe Filiberto Serraino, Federica Jiritano, Davide Costa, Nicola Ielapi, Desirèe Napolitano, Pasquale Mastroroberto, Umberto Marcello Bracale, Michele Andreucci and Raffaele Serra

Biomolecules 2023, 13(4), 665; https://doi.org/10.3390/biom13040665 - 11 Apr 2023

Cited by 3 | Viewed by 1397

Abstract

Hypertrophic cardiomyopathy (HCM) is a genetic condition determined by an altered collagen turnover of the extracellular matrix. Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are abnormally released in patients with HCM. The purpose of this systematic review was to thoroughly summarize and discuss [...] Read more.

Hypertrophic cardiomyopathy (HCM) is a genetic condition determined by an altered collagen turnover of the extracellular matrix. Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are abnormally released in patients with HCM. The purpose of this systematic review was to thoroughly summarize and discuss the existing knowledge of MMPs profile in patients with HCM. All studies meeting the inclusion criteria (detailed data regarding MMPs in patients with HCM) were selected, after screening the literature from July 1975 to November 2022. Sixteen trials that enrolled a total of 892 participants were included. MMPs–particularly MMP2—levels were found higher in HCM patients compared to healthy subjects. MMPs were used as biomarkers after surgical and percutaneous treatments. Understanding the molecular processes that control the cardiac ECM’s collagen turnover allows for a non-invasive evaluation of HCM patients through the monitoring of MMPs and TIMPs. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 3.0)

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12 pages, 278 KiB

Open AccessSystematic Review

Metalloproteinases in Cardiac Surgery: A Systematic Review

by Giuseppe Filiberto Serraino, Federica Jiritano, Davide Costa, Nicola Ielapi, Domenica Battaglia, Umberto Marcello Bracale, Pasquale Mastroroberto, Michele Andreucci and Raffaele Serra

Biomolecules 2023, 13(1), 113; https://doi.org/10.3390/biom13010113 - 05 Jan 2023

Cited by 6 | Viewed by 1376

Abstract

The role of matrix metalloproteinases (MMPs) in routine cardiac operations including cardiopulmonary bypass (CPB) is still poorly explored. The purpose of this systematic review was to thoroughly summarize and discuss the existing knowledge of the MMP profile in cardiac surgery. All studies meeting [...] Read more.

The role of matrix metalloproteinases (MMPs) in routine cardiac operations including cardiopulmonary bypass (CPB) is still poorly explored. The purpose of this systematic review was to thoroughly summarize and discuss the existing knowledge of the MMP profile in cardiac surgery. All studies meeting the inclusion criteria (i.e., those reporting detailed data about MMP release during and after CPB) were selected after screening the literature published between July 1975 and August 2022. Fifteen trials that enrolled a total of 431 participants were included. MMP levels were found to be significantly correlated with CPB in all included studies. The gelatinases MMP-2 and MMP-9 were highly released in cardiac surgery with CPB. MMP-9 levels were found to be increased after CPB start and during the duration of CPB. Particularly, it is overexpressed both in the myocardial tissue and circulating in the bloodstream. Also, MMP-2 levels increased after CPB both in plasma and in myocardial tissue. MMP-7, MMP-8, and MMP-13 levels increased after CPB start and remained elevated up to 6 h later. Increased levels of MMPs were associated with adverse post-operative outcomes. Conversely, TIMP-1 decreased with CPB. Mechanical and pharmacological strategies were applied in two studies to analyze their effect on the inflammatory response to cardiac surgery and CPB and on postoperative outcomes. New targeted MMP inhibitor therapies could protect against systemic inflammatory response syndrome after CPB and should be the subject of future large prospective multicenter randomized clinical trials. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 3.0)

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