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Cells
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Matrix Metalloproteinases: From Structure to Function
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Matrix Metalloproteinases: From Structure to Function

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Motility and Adhesion".

Deadline for manuscript submissions: closed (20 December 2021) | Viewed by 32342

Special Issue Editors

Prof. Ghislain Opdenakker

E-Mail Website
Guest Editor
Laboratory of Immunobiology, Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, 3000 Leuven, Belgium
Interests: matrix metalloprotease-9; immunology; autoimmune diseases; inflammation; glycobiology; neutrophil biology; neuroinflammation
Dr. Jennifer Vandooren

E-Mail Website
Guest Editor
Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, KU Leuven, Herestraat 49-bus 1044, B-3000 Leuven, Belgium
Interests: proteolysis; inflammation; MMPs; neutrophils; innate immune system; protease inhibition; alpha-2-macroglobulin
Dr. Estefania Ugarte-Berzal

E-Mail Website
Guest Editor
Laboratory of Immunobiology, Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, 3000 Leuven, Belgium
Interests: autoimmune diseases; lupus; immunoglobulins; leukemia

Special Issue Information

Dear Colleagues,

Matrix metalloproteases (MMPs) are a family of secreted or cell-bound zinc-dependent endopeptidases. While originally considered as matrix-remodelling enzymes (hence their name), many studies have revealed that MMPs have broader roles than matrix remodelling. Indeed, MMP substrates are found in the extracellular milieu associated with the cell membrane and even intracellularly. Not surprisingly, the impact of MMPs on life is broad, ranging from vital physiological processes to the initiation and progression of diseases. MMPs are essential for morphogenic and developmental processes including blood vessel remodelling and bone ossification. They are needed for normal tissue function and contribute to wound healing and repair, reproductive processes, and the innate immune defence. In contrast, the aberrant regulation of MMPs contributes to disease progression, for example, (auto-)inflammation (e.g., asthma and rheumatoid arthritis), neuropathology (e.g., multiple sclerosis), and cancer.

Although the significance of MMPs in homeostasis and disease is clear, fundamental information on MMP structures and in vivo functions remains limited. The importance of such information was illustrated several decades ago. Based on the finding of MMP up-regulation in malignant cancer tissue, it was suggested that MMPs are crucial to tumor growth and metastasis. Hence, several synthetic broad-spectrum MMP inhibitors were developed and evaluated in human clinical trials. Unfortunately, the outcomes were disappointing due to poor bioavailability and severe side-effects. Over the years, we have learned that MMPs work beyond classical connective tissue remodeling, that MMPs are tightly and differentially regulated, that different MMPs have different roles and different substrates, that MMPs are multi-domain enzymes with unique domain functions, and that MMPs have actions devoid of their proteolytic activity. Therefore, it is clear that only a detailed and critical (re-)analysis of MMP structures and functions will yield information and insights for their successful exploitation as disease targets.

The aim of this Special Issue is to explore and summarize the latest developments in MMP research with a focus on structural biological aspects and their functional implications. We invite experts to contribute high-quality original papers, research communications, or reviews.  

Prof. Ghislain Opdenakker
Dr. Jennifer Vandooren
Dr. Estefania Ugarte-Berzal
Guest Editors

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. Cells is an international peer-reviewed open access semimonthly 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

  • matrix metalloproteases
  • proteolysis
  • immunology
  • cancer
  • extracellular matrix
  • disease
  • protease inhibition
  • infection
  • inhibitor

Published Papers (5 papers)

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Research

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22 pages, 45979 KiB  
Article
Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Echinoderms: Structure and Possible Functions
by Igor Yu. Dolmatov, Vladimir A. Nizhnichenko and Lyudmila S. Dolmatova
Cells 2021, 10(9), 2331; https://doi.org/10.3390/cells10092331 - 6 Sep 2021
Cited by 13 | Viewed by 3057
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Matrix Metalloproteinases: From Structure to Function)
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21 pages, 3921 KiB  
Article
Bivalent Inhibitor with Selectivity for Trimeric MMP-9 Amplifies Neutrophil Chemotaxis and Enables Functional Studies on MMP-9 Proteoforms
by Elisa Nuti, Armando Rossello, Doretta Cuffaro, Caterina Camodeca, Jens Van Bael, Dries van der Maat, Erik Martens, Pierre Fiten, Rafaela Vaz Sousa Pereira, Estefania Ugarte-Berzal, Mieke Gouwy, Ghislain Opdenakker and Jennifer Vandooren
Cells 2020, 9(7), 1634; https://doi.org/10.3390/cells9071634 - 7 Jul 2020
Cited by 12 | Viewed by 3156
Abstract
A fundamental part of the immune response to infection or injury is leukocyte migration. Matrix metalloproteinases (MMPs) are a class of secreted or cell-bound endopeptidases, implicated in every step of the process of inflammatory cell migration. Hence, specific inhibition of MMPs is an [...] Read more.
A fundamental part of the immune response to infection or injury is leukocyte migration. Matrix metalloproteinases (MMPs) are a class of secreted or cell-bound endopeptidases, implicated in every step of the process of inflammatory cell migration. Hence, specific inhibition of MMPs is an interesting approach to control inflammation. We evaluated the potential of a bivalent carboxylate inhibitor to selectively inhibit the trimeric proteoform of MMP-9 and compared this with a corresponding monovalent inhibitor. The bivalent inhibitor efficiently inhibited trimeric MMP-9 (IC50 = 0.1 nM), with at least 500-fold selectivity for MMP-9 trimers over monomers. Surprisingly, in a mouse model for chemotaxis, the bivalent inhibitor amplified leukocyte influxes towards lipopolysaccharide-induced inflammation. We verified by microscopic and flow cytometry analysis increased amounts of neutrophils. In a mouse model for endotoxin shock, mice treated with the bivalent inhibitor had significantly increased levels of MMP-9 in plasma and lungs, indicative for increased inflammation. In conclusion, we propose a new role for MMP-9 trimers in tempering excessive neutrophil migration. In addition, we have identified a small molecule inhibitor with a high selectivity for the trimeric proteoform of MMP-9, which will allow further research on the functions of MMP-9 proteoforms. Full article
(This article belongs to the Special Issue Matrix Metalloproteinases: From Structure to Function)
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Review

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25 pages, 1028 KiB  
Review
Extracellular Metalloproteinases in the Plasticity of Excitatory and Inhibitory Synapses
by Grzegorz Wiera and Jerzy W. Mozrzymas
Cells 2021, 10(8), 2055; https://doi.org/10.3390/cells10082055 - 11 Aug 2021
Cited by 16 | Viewed by 5385
Abstract
Long-term synaptic plasticity is shaped by the controlled reorganization of the synaptic proteome. A key component of this process is local proteolysis performed by the family of extracellular matrix metalloproteinases (MMPs). In recent years, considerable progress was achieved in identifying extracellular proteases involved [...] Read more.
Long-term synaptic plasticity is shaped by the controlled reorganization of the synaptic proteome. A key component of this process is local proteolysis performed by the family of extracellular matrix metalloproteinases (MMPs). In recent years, considerable progress was achieved in identifying extracellular proteases involved in neuroplasticity phenomena and their protein substrates. Perisynaptic metalloproteinases regulate plastic changes at synapses through the processing of extracellular and membrane proteins. MMP9 was found to play a crucial role in excitatory synapses by controlling the NMDA-dependent LTP component. In addition, MMP3 regulates the L-type calcium channel-dependent form of LTP as well as the plasticity of neuronal excitability. Both MMP9 and MMP3 were implicated in memory and learning. Moreover, altered expression or mutations of different MMPs are associated with learning deficits and psychiatric disorders, including schizophrenia, addiction, or stress response. Contrary to excitatory drive, the investigation into the role of extracellular proteolysis in inhibitory synapses is only just beginning. Herein, we review the principal mechanisms of MMP involvement in the plasticity of excitatory transmission and the recently discovered role of proteolysis in inhibitory synapses. We discuss how different matrix metalloproteinases shape dynamics and turnover of synaptic adhesome and signal transduction pathways in neurons. Finally, we discuss future challenges in exploring synapse- and plasticity-specific functions of different metalloproteinases. Full article
(This article belongs to the Special Issue Matrix Metalloproteinases: From Structure to Function)
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24 pages, 2134 KiB  
Review
MMP14 in Sarcoma: A Regulator of Tumor Microenvironment Communication in Connective Tissues
by Jordi Gonzalez-Molina, Silvia Gramolelli, Zehuan Liao, Joseph W. Carlson, Päivi M. Ojala and Kaisa Lehti
Cells 2019, 8(9), 991; https://doi.org/10.3390/cells8090991 - 28 Aug 2019
Cited by 52 | Viewed by 7729
Abstract
Sarcomas are deadly malignant tumors of mesenchymal origin occurring at all ages. The expression and function of the membrane-type matrix metalloproteinase MMP14 is closely related to the mesenchymal cell phenotype, and it is highly expressed in most sarcomas. MMP14 regulates the activity of [...] Read more.
Sarcomas are deadly malignant tumors of mesenchymal origin occurring at all ages. The expression and function of the membrane-type matrix metalloproteinase MMP14 is closely related to the mesenchymal cell phenotype, and it is highly expressed in most sarcomas. MMP14 regulates the activity of multiple extracellular and plasma membrane proteins, influencing cell–cell and cell–extracellular matrix (ECM) communication. This regulation mediates processes such as ECM degradation and remodeling, cell invasion, and cancer metastasis. Thus, a comprehensive understanding of the biology of MMP14 in sarcomas will shed light on the mechanisms controlling the key processes in these diseases. Here, we provide an overview of the function and regulation of MMP14 and we discuss their relationship with clinical and pre-clinical MMP14 data in both adult and childhood sarcomas. Full article
(This article belongs to the Special Issue Matrix Metalloproteinases: From Structure to Function)
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24 pages, 1305 KiB  
Review
The Rebirth of Matrix Metalloproteinase Inhibitors: Moving Beyond the Dogma
by Gregg B. Fields
Cells 2019, 8(9), 984; https://doi.org/10.3390/cells8090984 - 27 Aug 2019
Cited by 192 | Viewed by 11473
Abstract
The pursuit of matrix metalloproteinase (MMP) inhibitors began in earnest over three decades ago. Initial clinical trials were disappointing, resulting in a negative view of MMPs as therapeutic targets. As a better understanding of MMP biology and inhibitor pharmacokinetic properties emerged, it became [...] Read more.
The pursuit of matrix metalloproteinase (MMP) inhibitors began in earnest over three decades ago. Initial clinical trials were disappointing, resulting in a negative view of MMPs as therapeutic targets. As a better understanding of MMP biology and inhibitor pharmacokinetic properties emerged, it became clear that initial MMP inhibitor clinical trials were held prematurely. Further complicating matters were problematic conclusions drawn from animal model studies. The most recent generation of MMP inhibitors have desirable selectivities and improved pharmacokinetics, resulting in improved toxicity profiles. Application of selective MMP inhibitors led to the conclusion that MMP-2, MMP-9, MMP-13, and MT1-MMP are not involved in musculoskeletal syndrome, a common side effect observed with broad spectrum MMP inhibitors. Specific activities within a single MMP can now be inhibited. Better definition of the roles of MMPs in immunological responses and inflammation will help inform clinic trials, and multiple studies indicate that modulating MMP activity can improve immunotherapy. There is a U.S. Food and Drug Administration (FDA)-approved MMP inhibitor for periodontal disease, and several MMP inhibitors are in clinic trials, targeting a variety of maladies including gastric cancer, diabetic foot ulcers, and multiple sclerosis. It is clearly time to move on from the dogma of viewing MMP inhibition as intractable. Full article
(This article belongs to the Special Issue Matrix Metalloproteinases: From Structure to Function)
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