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New Insights on ADAMTS Proteases in Health

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A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 24713

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Special Issue Editor

Prof. Dr. Alister C. Ward

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Guest Editor

School of Medicine, Centre of Molecular and Medical Research, Deakin University, Waurn Ponds, VIC 3216, Australia
Interests: cytokines; cell signaling; JAK-STAT pathway; SOCS; hematopoiesis; leukocytes lymphocytes; leukemia; lymphoma
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The development and on-going homeostasis of an organism is complex and involves multiple layers of control. While much of this occurs within individual cells, it is clear that these cells receive a range of external signals, with a growing awareness of the importance of the interactions with the extracellular matrix (ECM).

The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) proteins are multidomain proteases that act extracellularly, being crucial for shaping the ECM that impacts cell migration and other functions. Collectively, the 19 ADAMTS family members serve to facilitate development and homeostasis, and have been implicated in a variety of diseases, such as inflammation, arthritis, and oncogenesis.

This Edition celebrates the ADAMTS family, and aims to detail both their commonality and diversity, with a focus on their role in development and disease.

Prof. Alister C. Ward
Guest Editor

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Keywords

ADAMTS
proteases
extracellular matrix
cell–cell signaling
development
disease
cancer
immunology
hematology

Published Papers (7 papers)

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Research

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17 pages, 12655 KiB

Open AccessArticle

ADAMTS1 Supports Endothelial Plasticity of Glioblastoma Cells with Relevance for Glioma Progression

by Orlando Serrano-Garrido, Carlos Peris-Torres, Silvia Redondo-García, Helena G. Asenjo, María del Carmen Plaza-Calonge, José Luis Fernandez-Luna and Juan Carlos Rodríguez-Manzaneque

Biomolecules 2021, 11(1), 44; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11010044 - 31 Dec 2020

Cited by 7 | Viewed by 2913

Abstract

Gliomas in general and the more advanced glioblastomas (GBM) in particular are the most usual tumors of the central nervous system with poor prognosis. GBM patients develop resistance to distinct therapies, in part due to the existence of tumor cell subpopulations with stem-like properties that participate in trans-differentiation events. Within the complex tumor microenvironment, the involvement of extracellular proteases remains poorly understood. The extracellular protease ADAMTS1 has already been reported to contribute to the plasticity of cancer cells. Accordingly, this basic knowledge and the current availability of massive sequencing data from human gliomas, reinforced the development of this work. We first performed an in silico study of ADAMTS1 and endothelial markers in human gliomas, providing the basis to further assess these molecules in several primary glioblastoma-initiating cells and established GBM cells with the ability to acquire an endothelial-like phenotype. Using a co-culture approach of endothelial and GBM cells, we noticed a relevant function of ADAMTS1 in GBM cells leading the organization of endothelial-like networks and, even more significantly, we found a blockade of the formation of tumor-spheres and a deficient response to hypoxia in the absence of ADAMTS1. Our data support a chief role of this protease modulating the phenotypic plasticity of GBM. Full article

(This article belongs to the Special Issue New Insights on ADAMTS Proteases in Health)

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16 pages, 4426 KiB

Open AccessArticle

ADAMTS-15 Has a Tumor Suppressor Role in Prostate Cancer

by Marley J. Binder, Scott McCoombe, Elizabeth D. Williams, Daniel R. McCulloch and Alister C. Ward

Biomolecules 2020, 10(5), 682; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10050682 - 28 Apr 2020

Cited by 21 | Viewed by 2843

Abstract

Extracellular matrix remodeling has emerged as an important factor in many cancers. Proteoglycans, including versican (VCAN), are regulated via cleavage by the proteolytic actions of A Disintegrin-like And Metalloproteinase domain with Thrombospondin-1 motif (ADAMTS) family members. Alterations in the balance between Proteoglycans and ADAMTS enzymes have been proposed to contribute to cancer progression. Here, we analyzed the expression of ADAMTS-15 in human prostate cancer, and investigated the effects of enforced expression in prostate cancer cell lines. ADAMTS-15 was found to be expressed in human prostate cancer biopsies with evidence of co-localization with VCAN and its bioactive cleavage fragment versikine. Enforced expression of ADAMTS-15, but not a catalytically-inactive version, decreased cell proliferation and migration of the ‘castrate-resistant’ PC3 prostate cancer cell line in vitro, with survival increased. Analysis of ‘androgen-responsive’ LNCaP prostate cancer cells in vivo in NOD/SCID mice revealed that ADAMTS-15 expression caused slower growing tumors, which resulted in increased survival. This was not observed in castrated mice or with cells expressing catalytically-inactive ADAMTS-15. Collectively, this research identifies the enzymatic function of ADAMTS-15 as having a tumor suppressor role in prostate cancer, possibly in concert with androgens, and that VCAN represents a likely key substrate, highlighting potential new options for the clinic. Full article

(This article belongs to the Special Issue New Insights on ADAMTS Proteases in Health)

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15 pages, 918 KiB

Open AccessArticle

Genomic Landscape and Mutational Spectrum of ADAMTS Family Genes in Mendelian Disorders Based on Gene Evidence Review for Variant Interpretation

by John Hoon Rim, Yo Jun Choi and Heon Yung Gee

Biomolecules 2020, 10(3), 449; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10030449 - 13 Mar 2020

Cited by 4 | Viewed by 3105

Abstract

ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) are a family of multidomain extracellular protease enzymes with 19 members. A growing number of ADAMTS family gene variants have been identified in patients with various hereditary diseases. To understand the genomic landscape and mutational spectrum of ADAMTS family genes, we evaluated all reported variants in the ClinVar database and Human Gene Mutation Database (HGMD), as well as recent literature on Mendelian hereditary disorders associated with ADAMTS family genes. Among 1089 variants in 14 genes reported in public databases, 307 variants previously suggested for pathogenicity in Mendelian diseases were comprehensively re-evaluated using the American College of Medical Genetics and Genomics (ACMG) 2015 guideline. A total of eight autosomal recessive genes were annotated as being strongly associated with specific Mendelian diseases, including two recently discovered genes (ADAMTS9 and ADAMTS19) for their causality in congenital diseases (nephronophthisis-related ciliopathy and nonsyndromic heart valve disease, respectively). Clinical symptoms and affected organs were extremely heterogeneous among hereditary diseases caused by ADAMTS family genes, indicating phenotypic heterogeneity despite their structural and functional similarity. ADAMTS6 was suggested as presenting undiscovered pathogenic mutations responsible for novel Mendelian disorders. Our study is the first to highlight the genomic landscape of ADAMTS family genes, providing an appropriate genetic approach for clinical use. Full article

(This article belongs to the Special Issue New Insights on ADAMTS Proteases in Health)

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18 pages, 5972 KiB

Open AccessArticle

Treatment of Dystrophic mdx Mice with an ADAMTS-5 Specific Monoclonal Antibody Increases the Ex Vivo Strength of Isolated Fast Twitch Hindlimb Muscles

by Alex B. Addinsall, Leonard G. Forgan, Natasha L. McRae, Rhys W. Kelly, Penny L. McDonald, Bryony McNeil, Daniel R. McCulloch and Nicole Stupka

Biomolecules 2020, 10(3), 416; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10030416 - 7 Mar 2020

Cited by 8 | Viewed by 4129

Abstract

Aberrant extracellular matrix synthesis and remodeling contributes to muscle degeneration and weakness in Duchenne muscular dystrophy (DMD). ADAMTS-5, a secreted metalloproteinase with catalytic activity against versican, is implicated in myogenesis and inflammation. Here, using the mdx mouse model of DMD, we report increased ADAMTS-5 expression in dystrophic hindlimb muscles, localized to regions of regeneration and inflammation. To investigate the pathophysiological significance of this, 4-week-old mdx mice were treated with an ADAMTS-5 monoclonal antibody (mAb) or IgG2c (IgG) isotype control for 3 weeks. ADAMTS-5 mAb treatment did not reduce versican processing, as protein levels of the cleaved versikine fragment did not differ between hindlimb muscles from ADAMTS-5 mAb or IgG treated mdx mice. Nonetheless, ADAMTS-5 blockade improved ex vivo strength of isolated fast extensor digitorum longus, but not slow soleus, muscles. The underpinning mechanism may include modulation of regenerative myogenesis, as ADAMTS-5 blockade reduced the number of recently repaired desmin positive myofibers without affecting the number of desmin positive muscle progenitor cells. Treatment with the ADAMTS-5 mAb did not significantly affect markers of muscle damage, inflammation, nor fiber size. Altogether, the positive effects of ADAMTS-5 blockade in dystrophic muscles are fiber-type-specific and independent of versican processing. Full article

(This article belongs to the Special Issue New Insights on ADAMTS Proteases in Health)

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Review

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14 pages, 1128 KiB

Open AccessReview

The ADAMTS/Fibrillin Connection: Insights into the Biological Functions of ADAMTS10 and ADAMTS17 and Their Respective Sister Proteases

by Stylianos Z. Karoulias, Nandaraj Taye, Sarah Stanley and Dirk Hubmacher

Biomolecules 2020, 10(4), 596; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10040596 - 12 Apr 2020

Cited by 24 | Viewed by 5155

Abstract

Secreted a disintegrin-like and metalloprotease with thrombospondin type 1 motif (ADAMTS) proteases play crucial roles in tissue development and homeostasis. The biological and pathological functions of ADAMTS proteases are determined broadly by their respective substrates and their interactions with proteins in the pericellular and extracellular matrix. For some ADAMTS proteases, substrates have been identified and substrate cleavage has been implicated in tissue development and in disease. For other ADAMTS proteases, substrates were discovered in vitro, but the role of these proteases and the consequences of substrate cleavage in vivo remains to be established. Mutations in ADAMTS10 and ADAMTS17 cause Weill–Marchesani syndrome (WMS), a congenital syndromic disorder that affects the musculoskeletal system (short stature, pseudomuscular build, tight skin), the eyes (lens dislocation), and the heart (heart valve abnormalities). WMS can also be caused by mutations in fibrillin-1 (FBN1), which suggests that ADAMTS10 and ADAMTS17 cooperate with fibrillin-1 in a common biological pathway during tissue development and homeostasis. Here, we compare and contrast the biochemical properties of ADAMTS10 and ADAMTS17 and we summarize recent findings indicating potential biological functions in connection with fibrillin microfibrils. We also compare ADAMTS10 and ADAMTS17 with their respective sister proteases, ADAMTS6 and ADAMTS19; both were recently linked to human disorders distinct from WMS. Finally, we propose a model for the interactions and roles of these four ADAMTS proteases in the extracellular matrix. Full article

(This article belongs to the Special Issue New Insights on ADAMTS Proteases in Health)

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17 pages, 1093 KiB

Open AccessReview

New Insights into ADAMTS Metalloproteases in the Central Nervous System

by Yamina Mohamedi, Tania Fontanil, Teresa Cobo, Santiago Cal and Alvaro J. Obaya

Biomolecules 2020, 10(3), 403; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10030403 - 5 Mar 2020

Cited by 17 | Viewed by 4194

Abstract

Components of the extracellular matrix (ECM) are key players in regulating cellular functions throughout the whole organism. In fact, ECM components not only participate in tissue organization but also contribute to processes such as cellular maintenance, proliferation, and migration, as well as to support for various signaling pathways. In the central nervous system (CNS), proteoglycans of the lectican family, such as versican, aggrecan, brevican, and neurocan, are important constituents of the ECM. In recent years, members of this family have been found to be involved in the maintenance of CNS homeostasis and to participate directly in processes such as the organization of perineural nets, the regulation of brain plasticity, CNS development, brain injury repair, axonal guidance, and even the altering of synaptic responses. ADAMTSs are a family of “A disintegrin and metalloproteinase with thrombospondin motifs” proteins that have been found to be involved in a multitude of processes through the degradation of lecticans and other proteoglycans. Recently, alterations in ADAMTS expression and activity have been found to be involved in neuronal disorders such as stroke, neurodegeneration, schizophrenia, and even Alzheimer’s disease, which in turn may suggest their potential use as therapeutic targets. Herein, we summarize the different roles of ADAMTSs in regulating CNS events through interactions and the degradation of ECM components (more specifically, the lectican family of proteoglycans). Full article

(This article belongs to the Special Issue New Insights on ADAMTS Proteases in Health)

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Other

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2 pages, 478 KiB

Open AccessErratum

Erratum: Treatment of Dystrophic mdx Mice with an ADAMTS-5 Specific Monoclonal Antibody Increases the Ex Vivo Strength of Isolated Fast Twitch Hindlimb Muscles. Biomolecules 2020, 10, 416

by Alex B. Addinsall, Leonard G. Forgan, Natasha L. McRae, Rhys W. Kelly, Penny L. McDonald, Bryony McNeill, Daniel R. McCulloch and Nicole Stupka

Biomolecules 2020, 10(7), 1053; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10071053 - 15 Jul 2020

Cited by 2 | Viewed by 1491

Abstract

The authors wish to make a change to this published paper [...] Full article

(This article belongs to the Special Issue New Insights on ADAMTS Proteases in Health)

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