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Biomolecules
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Matrix Metalloproteinases in Health and Disease 2.0
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Matrix Metalloproteinases in Health and Disease 2.0

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biological Factors".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 21245

Special Issue Editor

Prof. Dr. Raffaele Serra

E-Mail Website
Guest Editor
Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
Interests: cardiovascular disease; vascular surgery; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Matrix metalloproteinases (MMPs) are members of an enzyme family that are critical for maintaining tissue allostasis. MMPs can catalyze the normal turnover of extracellular matrix (ECM) together with other metalloproteinases such as the ADAMs (a disintegrin and metalloproteinase) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif) families. MMP activity is also regulated by a group of endogenous proteins, called tissue inhibitor of metalloproteinases (TIMPs). All these proteins have a pivotal role in normal physiological processes involving ECM remodeling, such as wound healing, embryogenesis, angiogenesis, bone remodeling, immunity and the female reproductive cycle. An imbalance in the expression or activity of MMPs can also have important consequences in diseases such as cancer, cardiovascular disease, peripheral vascular disease, chronic leg ulcers, multiple sclerosis and others.

In the last few years, MMPs have been found to have an important role in the field of Precision Medicine as they may serve as biormakers that may predict an individual’s disease predisposition, state or progression. MMPs are also thought to be a sensible target for molecular therapy.

The aim of this Special Issue is to explore the most recent findings in this field that may have an impact in health care systems.

Prof. Dr. Raffaele Serra
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • MMPs
  • ADAMs
  • ADAMTs
  • TIMPs
  • cardiovascular disease
  • peripheral vascular disease
  • wound healing
  • chronic leg ulcers
  • cancer
  • multiple sclerosis

Published Papers (8 papers)

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Editorial

Jump to: Research, Review, Other

2 pages, 174 KiB  
Editorial
Matrix Metalloproteinases in Health and Disease 2.0
by Raffaele Serra
Biomolecules 2022, 12(9), 1190; https://doi.org/10.3390/biom12091190 - 27 Aug 2022
Cited by 1 | Viewed by 1127
Abstract
Matrix metalloproteinases (MMPs) are members of an enzyme family that are critical for maintaining tissue allostasis [...] Full article
(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 2.0)

Research

Jump to: Editorial, Review, Other

14 pages, 2170 KiB  
Article
Defining the Protease and Protease Inhibitor (P/PI) Proteomes of Healthy and Diseased Human Skin by Modified Systematic Review
by Callum Stewart-McGuinness, Christopher I. Platt, Matiss Ozols, Brian Goh, Tamara W. Griffiths and Michael J. Sherratt
Biomolecules 2022, 12(3), 475; https://doi.org/10.3390/biom12030475 - 20 Mar 2022
Cited by 4 | Viewed by 3258
Abstract
Proteases and protease inhibitors (P/PIs) are involved in many biological processes in human skin, yet often only specific families or related groups of P/PIs are investigated. Proteomics approaches, such as mass spectrometry, can define proteome signatures (including P/PIs) in tissues; however, they struggle [...] Read more.
Proteases and protease inhibitors (P/PIs) are involved in many biological processes in human skin, yet often only specific families or related groups of P/PIs are investigated. Proteomics approaches, such as mass spectrometry, can define proteome signatures (including P/PIs) in tissues; however, they struggle to detect low-abundance proteins. To overcome these issues, we aimed to produce a comprehensive proteome of all P/PIs present in normal and diseased human skin, in vivo, by carrying out a modified systematic review using a list of P/PIs from MEROPS and combining this with key search terms in Web of Science. Resulting articles were manually reviewed against inclusion/exclusion criteria and a dataset constructed. This study identified 111 proteases and 77 protease inhibitors in human skin, comprising the serine, metallo-, cysteine and aspartic acid catalytic families of proteases. P/PIs showing no evidence of catalytic activity or protease inhibition, were designated non-peptidase homologs (NPH), and no reported protease inhibitory activity (NRPIA), respectively. MMP9 and TIMP1 were the most frequently published P/PIs and were reported in normal skin and most skin disease groups. Normal skin and diseased skin showed significant overlap with respect to P/PI profile; however, MMP23 was identified in several skin disease groups, but was absent in normal skin. The catalytic profile of P/PIs in wounds, scars and solar elastosis was distinct from normal skin, suggesting that a different group of P/PIs is responsible for disease progression. In conclusion, this study uses a novel approach to provide a comprehensive inventory of P/PIs in normal and diseased human skin reported in our database. The database may be used to determine either which P/PIs are present in specific diseases or which diseases individual P/PIs may influence. Full article
(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 2.0)
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15 pages, 1301 KiB  
Article
Genetic Variants of Matrix Metalloproteinase and Sepsis: The Need Speed Study
by Nicola Fiotti, Filippo Mearelli, Filippo Giorgio Di Girolamo, Luigi Mario Castello, Alessio Nunnari, Salvatore Di Somma, Enrico Lupia, Efrem Colonetti, Maria Lorenza Muiesan, Giuseppe Montrucchio, Carlo Giansante, Gian Carlo Avanzi and Gianni Biolo
Biomolecules 2022, 12(2), 279; https://doi.org/10.3390/biom12020279 - 9 Feb 2022
Cited by 3 | Viewed by 1834
Abstract
Many causal mechanisms in sepsis susceptibility are largely unknown and the functional genetic polymorphisms (GP) of matrix metalloproteinases (MMPs) and their natural tissue inhibitor of MMPs (TIMP1) could play a role in its development. GPs of MMPs and TIMP (namely MMP-1 rs1799750, MMP-3 [...] Read more.
Many causal mechanisms in sepsis susceptibility are largely unknown and the functional genetic polymorphisms (GP) of matrix metalloproteinases (MMPs) and their natural tissue inhibitor of MMPs (TIMP1) could play a role in its development. GPs of MMPs and TIMP (namely MMP-1 rs1799750, MMP-3 rs3025058, MMP-8 rs11225395, MMP-9 rs2234681, and TIMP-1 rs4898) have been compared in 1058 patients with suspected sepsis to assess the association with susceptibility and etiology of sepsis. Prevalence of MMP8 rs11225395 G/G genotype was higher in sepsis patients than in those with non-infective Systemic Inflammatory Reaction Syndrome (35.6 vs. 26%, hazard ratio, HR 1.56, 95% C.I. 1.04–2.42, p = 0.032). G/G patients developed less hyperthermia (p = 0.041), even after stratification for disease severity (p = 0.003). Patients carrying the 6A allele in MMP3 rs3025058 had a higher probability of microbiologically-proven sepsis (HR 1.4. 95%C.I. 1.01–1.94, p = 0.044), particularly when due to virus (H.R. 2.14, 95% C.I. 1.06–4.31, p = 0.046), while MMP-1 G/G genotype patients carried a higher risk for intracellular bacteria (Chlamydia, Mycoplasma, and Legionella, H.R. 6.46, 95% C.I. 1.58–26.41, p = 0.003). Neither severity of sepsis at presentation, nor 30-day mortality were influenced by the investigated variants or their haplotype. MMP8 rs11225395 G/G carriers have lower temperature at presentation and a more than 50% increased susceptibility to sepsis. Among patients with sepsis, carriers of MMP1 rs1799750 G/G have an increased susceptibility for intracellular pathogen infections, while virus serology is more often positive in those with the MMP3 rs3025058 A/A genotype. Full article
(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 2.0)
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11 pages, 1929 KiB  
Article
Relationship between Cerebrospinal Fluid Matrix Metalloproteinases Levels and Brain Amyloid Deposition in Mild Cognitive Impairment
by Yuuki Sasaki, Noriyuki Kimura, Yasuhiro Aso, Kenichi Yabuuchi, Miki Aikawa and Etsuro Matsubara
Biomolecules 2021, 11(10), 1496; https://doi.org/10.3390/biom11101496 - 11 Oct 2021
Cited by 4 | Viewed by 2121
Abstract
This study aimed to explore whether cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs), and their inhibitors (TIMPs) were associated with brain amyloid deposition, cortical glucose metabolism, and white matter lesions (WMLs) in individuals with amnestic mild cognitive impairment (MCI). A total of [...] Read more.
This study aimed to explore whether cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs), and their inhibitors (TIMPs) were associated with brain amyloid deposition, cortical glucose metabolism, and white matter lesions (WMLs) in individuals with amnestic mild cognitive impairment (MCI). A total of 33 individuals with amnestic MCI (mean age, 75.6 years) underwent 11C-Pittsburgh compound B positron emission tomography (PiB-PET), 18F-fluorodeoxyglucose positron emission tomography, magnetic resonance imaging or computed tomography, and CSF analysis. PET uptake of the frontal and temporoparietal lobes and posterior cingulate gyrus was assessed using the cerebellar cortex as the reference region. WMLs were assessed by the Fazekas scale. CSF levels of MMPs and TIMPs were measured with bead-based multiplex assays. After adjusting for covariates, multiple linear regression analysis showed that CSF levels of MMP-2 were negatively correlated with global PiB uptake (p = 0.035), especially in the parietotemporal lobe and posterior cingulate gyrus (p = 0.016 and p = 0.041, respectively). Moreover, CSF levels of MMP-7 were positively correlated with the severity of WMLs (p = 0.033). CSF levels of MMP-2 and MMP-7 are associated with brain amyloid deposition and severity of WMLs, respectively. These findings provide valuable insights into the role of MMPs in amyloid β catabolism and blood–brain barrier integration at the MCI stage. Full article
(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 2.0)
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Review

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16 pages, 492 KiB  
Review
ADAMTS Proteins and Vascular Remodeling in Aortic Aneurysms
by Zakaria Mougin, Julia Huguet Herrero, Catherine Boileau and Carine Le Goff
Biomolecules 2022, 12(1), 12; https://doi.org/10.3390/biom12010012 - 22 Dec 2021
Cited by 5 | Viewed by 3852
Abstract
Extracellular matrix (ECM) in the vascular wall is a highly dynamic structure composed of a set of different molecules such as elastins, collagens, fibronectin (Fn), laminins, proteoglycans, and polysaccharides. ECM undergoes remodeling processes to regulate vascular smooth muscle and endothelial cells’ proliferation, differentiation, [...] Read more.
Extracellular matrix (ECM) in the vascular wall is a highly dynamic structure composed of a set of different molecules such as elastins, collagens, fibronectin (Fn), laminins, proteoglycans, and polysaccharides. ECM undergoes remodeling processes to regulate vascular smooth muscle and endothelial cells’ proliferation, differentiation, and adhesion. Abnormalities affecting the ECM can lead to alteration in cellular behavior and from this, this can conduce to the development of pathologies. Metalloproteases play a key role in maintaining the homeostasis of ECM by mediating the cleavage of different ECM components. There are different types of metalloproteases: matrix metalloproteinases (MMPs), disintegrin and metalloproteinases (ADAMs), and ADAMs with thrombospondin motifs (ADAMTSs). ADAMTSs have been found to participate in cardiovascular physiology and diseases and specifically in aortic aneurysms. This review aims to decipher the potential role of ADAMTS proteins in the physiopathologic development of Thoracic Aortic Aneurysms (TAA) and Abdominal Aortic Aneurysms (AAA). This review will focus on what is known on the ADAMTS family involved in human aneurysms from human tissues to mouse models. The recent findings on THSD4 (encoding ADAMTSL6) mutations in TAA give a new insight on the involvement of the ADAMTS family in TAA. Full article
(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 2.0)
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10 pages, 380 KiB  
Review
Matrix Metalloproteinases as Biomarkers and Treatment Targets in Mesothelioma: A Systematic Review
by Danijela Štrbac and Vita Dolžan
Biomolecules 2021, 11(9), 1272; https://doi.org/10.3390/biom11091272 - 25 Aug 2021
Cited by 3 | Viewed by 1987
Abstract
Metalloproteinases (MMPs) have an important role in tissue remodeling and have been shown to have an effect on tumor progression, invasion, metastasis formation, and apoptosis in several tumors, including mesothelioma. Mesothelioma is a rare tumor arising from pleura and peritoneum and is frequently [...] Read more.
Metalloproteinases (MMPs) have an important role in tissue remodeling and have been shown to have an effect on tumor progression, invasion, metastasis formation, and apoptosis in several tumors, including mesothelioma. Mesothelioma is a rare tumor arising from pleura and peritoneum and is frequently associated with asbestos exposure. We have performed a systematic search of PubMed.gov and ClinicalTrials.gov databases to retrieve and review three groups of studies: studies of MMPs expression in tumor tissue or body fluids in patients with mesothelioma, studies of MMPs genetic variability, and studies of MMPs as potential novel drug targets in mesothelioma. Several studies of MMPs in mesothelioma tissues reported a link between higher expression levels of commonly studied MMPs and clinical parameters, such as overall survival. Fewer studies have investigated genetic variability of MMP genes. Nevertheless, these studies suggested that certain genetic variants in MMP genes can have either protective or tumor-promoting effects on mesothelioma patients. MMPs have been also reported as novel drug targets, but so far no clinical trials of MMP inhibitors are registered in mesothelioma. In conclusion, MMPs play an important role in mesothelioma, but further studies are needed to elucidate the potentials of MMPs as biomarkers and drug targets in mesothelioma. Full article
(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 2.0)
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13 pages, 2539 KiB  
Review
Aortic Aneurysms, Chronic Kidney Disease and Metalloproteinases
by Michele Andreucci, Michele Provenzano, Teresa Faga, Ashour Michael, Gemma Patella, Pasquale Mastroroberto, Giuseppe Filiberto Serraino, Umberto Marcello Bracale, Nicola Ielapi and Raffaele Serra
Biomolecules 2021, 11(2), 194; https://doi.org/10.3390/biom11020194 - 30 Jan 2021
Cited by 24 | Viewed by 3219
Abstract
Metalloproteinases (MPs) are proteolytic enzymes involved in extracellular matrix deposition, regulation of cellular signals of inflammation, proliferation, and apoptosis. Metalloproteinases are classified into three families: Matrix-MPs (MMPs), A-Disintegrin-and-Metalloprotease (ADAMs), and the A-Disintegrin-and-Metalloproteinase-with-Thrombospondin-1-like-Domains (ADAMTS). Previous studies showed that MPs are involved in the development [...] Read more.
Metalloproteinases (MPs) are proteolytic enzymes involved in extracellular matrix deposition, regulation of cellular signals of inflammation, proliferation, and apoptosis. Metalloproteinases are classified into three families: Matrix-MPs (MMPs), A-Disintegrin-and-Metalloprotease (ADAMs), and the A-Disintegrin-and-Metalloproteinase-with-Thrombospondin-1-like-Domains (ADAMTS). Previous studies showed that MPs are involved in the development of aortic aneurysms (AA) and, concomitantly, in the onset of chronic kidney disease (CKD). CKD has been, per se, associated with an increased risk for AA. The aim of this review is to examine the pathways that may associate MPs with CKD and AA. Several MMPs, such as MMP-2, -8, -9, and TIMP-1 have been shown to damage the AA wall and to have a toxic effect on renal tubular cells, leading to fibrosis. Similarly, ADAM10 and 17 have been shown to degrade collagen in the AA wall and to worsen kidney function via pro-inflammatory stimuli, the impairment of the Renin-Angiotensin-Aldosterone System, and the degradation of structural proteins. Moreover, MMP-2 and -9 inhibitors reduced aneurysm growth and albuminuria in experimental and human studies. It would be important, in the future, to expand research on MPs from both a prognostic, namely, to refine risk stratification in CKD patients, and a predictive perspective, likely to improve prognosis in response to targeted treatments. Full article
(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 2.0)
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Other

10 pages, 905 KiB  
Systematic Review
A Scoping Review of the Role of Metalloproteinases in the Pathogenesis of Autoimmune Pemphigus and Pemphigoid
by Nicola Cirillo and Stephen S. Prime
Biomolecules 2021, 11(10), 1506; https://doi.org/10.3390/biom11101506 - 13 Oct 2021
Cited by 15 | Viewed by 2574
Abstract
Pemphigus and pemphigoid diseases are potentially life-threatening autoimmune blistering disorders that are characterized by intraepithelial and subepithelial blister formation, respectively. In both disease groups, skin and/or mucosal blistering develop as a result of a disruption of intercellular adhesion (pemphigus) and cell-extracellular matrix (ECM) [...] Read more.
Pemphigus and pemphigoid diseases are potentially life-threatening autoimmune blistering disorders that are characterized by intraepithelial and subepithelial blister formation, respectively. In both disease groups, skin and/or mucosal blistering develop as a result of a disruption of intercellular adhesion (pemphigus) and cell-extracellular matrix (ECM) adhesion (pemphigoid). Given that metalloproteinases can target cell adhesion molecules, the purpose of the present study was to investigate the role of these enzymes in the pathogenesis of these bullous dermatoses. Studies examining MMPs (matrix metalloproteinases) and the ADAM (a disintegrin and metalloproteinase) family of proteases in pemphigus and pemphigoid were selected from articles published in the repository of the National Library of Medicine (MEDLINE/PubMed) and bioRxiv. Multiple phases of screening were conducted, and relevant data were extracted and tabulated, with 29 articles included in the final qualitative analysis. The majority of the literature investigated the role of specific components of the MMP family primarily in bullous pemphigoid (BP) whereas studies that focused on pemphigus were rarer. The most commonly studied metalloproteinase was MMP-9 followed by MMP-2; other MMPs included MMP-1, MMP-3, MMP-8, MMP-12 and MMP-13. Molecules related to MMPs were also included, namely, ADAM5, 8, 10, 15, 17, together with TIMP-1 and TIMP-3. The results demonstrated that ADAM10 and MMP-9 activity is necessary for blister formation in experimental models of pemphigus vulgaris (PV) and BP, respectively. The data linking MMPs to the pathogenesis of experimental BP were relatively strong but the evidence for involvement of metalloproteinases in PV was more tentative. These molecules represent potential candidates for the development of mechanism-based treatments of these blistering diseases. Full article
(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 2.0)
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