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  1. Article ; Online: Proteolysis of fibrillin-2 microfibrils is essential for normal skeletal development

    Timothy J Mead / Daniel R Martin / Lauren W Wang / Stuart A Cain / Cagri Gulec / Elisabeth Cahill / Joseph Mauch / Dieter Reinhardt / Cecilia Lo / Clair Baldock / Suneel S Apte

    eLife, Vol

    2022  Volume 11

    Abstract: The embryonic extracellular matrix (ECM) undergoes transition to mature ECM as development progresses, yet few mechanisms ensuring ECM proteostasis during this period are known. Fibrillin microfibrils are macromolecular ECM complexes serving structural ... ...

    Abstract The embryonic extracellular matrix (ECM) undergoes transition to mature ECM as development progresses, yet few mechanisms ensuring ECM proteostasis during this period are known. Fibrillin microfibrils are macromolecular ECM complexes serving structural and regulatory roles. In mice, Fbn1 and Fbn2, encoding the major microfibrillar components, are strongly expressed during embryogenesis, but fibrillin-1 is the major component observed in adult tissue microfibrils. Here, analysis of Adamts6 and Adamts10 mutant mouse embryos, lacking these homologous secreted metalloproteases individually and in combination, along with in vitro analysis of microfibrils, measurement of ADAMTS6-fibrillin affinities and N-terminomics discovery of ADAMTS6-cleaved sites, identifies a proteostatic mechanism contributing to postnatal fibrillin-2 reduction and fibrillin-1 dominance. The lack of ADAMTS6, alone and in combination with ADAMTS10 led to excess fibrillin-2 in perichondrium, with impaired skeletal development defined by a drastic reduction of aggrecan and cartilage link protein, impaired BMP signaling in cartilage, and increased GDF5 sequestration in fibrillin-2-rich tissue. Although ADAMTS6 cleaves fibrillin-1 and fibrillin-2 as well as fibronectin, which provides the initial scaffold for microfibril assembly, primacy of the protease-substrate relationship between ADAMTS6 and fibrillin-2 was unequivocally established by reversal of the defects in Adamts6-/- embryos by genetic reduction of Fbn2, but not Fbn1.
    Keywords extracellular matrix ; Protease ; ADAMTS ; proteolysis ; fibrillin ; skeletal development ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: The secreted protease Adamts18 links hormone action to activation of the mammary stem cell niche

    Dalya Ataca / Patrick Aouad / Céline Constantin / Csaba Laszlo / Manfred Beleut / Marie Shamseddin / Renuga Devi Rajaram / Rachel Jeitziner / Timothy J. Mead / Marian Caikovski / Philipp Bucher / Giovanna Ambrosini / Suneel S. Apte / Cathrin Brisken

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 16

    Abstract: How hormonal signaling in the mammary epithelium controls the surrounding extracellular matrix is unclear. Here, the authors show that a secreted protease, Adamts18, induced by upstream estrogen-progesterone activated Wnt4 in myoepithelial cells, ... ...

    Abstract How hormonal signaling in the mammary epithelium controls the surrounding extracellular matrix is unclear. Here, the authors show that a secreted protease, Adamts18, induced by upstream estrogen-progesterone activated Wnt4 in myoepithelial cells, remodels the basement membrane and contributes to mammary epithelial stemness.
    Keywords Science ; Q
    Language English
    Publishing date 2020-03-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: The secreted protease Adamts18 links hormone action to activation of the mammary stem cell niche

    Dalya Ataca / Patrick Aouad / Céline Constantin / Csaba Laszlo / Manfred Beleut / Marie Shamseddin / Renuga Devi Rajaram / Rachel Jeitziner / Timothy J. Mead / Marian Caikovski / Philipp Bucher / Giovanna Ambrosini / Suneel S. Apte / Cathrin Brisken

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 16

    Abstract: How hormonal signaling in the mammary epithelium controls the surrounding extracellular matrix is unclear. Here, the authors show that a secreted protease, Adamts18, induced by upstream estrogen-progesterone activated Wnt4 in myoepithelial cells, ... ...

    Abstract How hormonal signaling in the mammary epithelium controls the surrounding extracellular matrix is unclear. Here, the authors show that a secreted protease, Adamts18, induced by upstream estrogen-progesterone activated Wnt4 in myoepithelial cells, remodels the basement membrane and contributes to mammary epithelial stemness.
    Keywords Science ; Q
    Language English
    Publishing date 2020-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Massive aggrecan and versican accumulation in thoracic aortic aneurysm and dissection

    Frank S. Cikach / Christopher D. Koch / Timothy J. Mead / Josephine Galatioto / Belinda B. Willard / Kelly B. Emerton / Matthew J. Eagleton / Eugene H. Blackstone / Francesco Ramirez / Eric E. Roselli / Suneel S. Apte

    JCI Insight, Vol 3, Iss

    2018  Volume 5

    Abstract: Proteoglycan accumulation is a hallmark of medial degeneration in thoracic aortic aneurysm and dissection (TAAD). Here, we defined the aortic proteoglycanome using mass spectrometry, and based on the findings, investigated the large aggregating ... ...

    Abstract Proteoglycan accumulation is a hallmark of medial degeneration in thoracic aortic aneurysm and dissection (TAAD). Here, we defined the aortic proteoglycanome using mass spectrometry, and based on the findings, investigated the large aggregating proteoglycans aggrecan and versican in human ascending TAAD and a mouse model of severe Marfan syndrome. The aortic proteoglycanome comprises 20 proteoglycans including aggrecan and versican. Antibodies against these proteoglycans intensely stained medial degeneration lesions in TAAD, contrasting with modest intralamellar staining in controls. Aggrecan, but not versican, was increased in longitudinal analysis of Fbn1mgR/mgR aortas. TAAD and Fbn1mgR/mgR aortas had increased aggrecan and versican mRNAs, and reduced expression of a key proteoglycanase gene, ADAMTS5, was seen in TAAD. Fbn1mgR/mgR mice with ascending aortic dissection and/or rupture had dramatically increased aggrecan staining compared with mice without these complications. Thus, aggrecan and versican accumulation in ascending TAAD occurs via increased synthesis and/or reduced proteolytic turnover, and correlates with aortic dissection/rupture in Fbn1mgR/mgR mice. Tissue swelling imposed by aggrecan and versican is proposed to be profoundly deleterious to aortic wall mechanics and smooth muscle cell homeostasis, predisposing to type-A dissections. These proteoglycans provide potential biomarkers for refined risk stratification and timing of elective aortic aneurysm repair.
    Keywords Vascular biology ; Medicine ; R
    Language English
    Publishing date 2018-03-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: ADAMTS9-Regulated Pericellular Matrix Dynamics Governs Focal Adhesion-Dependent Smooth Muscle Differentiation

    Timothy J. Mead / Yaoyao Du / Courtney M. Nelson / Ndeye-Aicha Gueye / Judith Drazba / Carolyn M. Dancevic / Mireille Vankemmelbeke / David J. Buttle / Suneel S. Apte

    Cell Reports, Vol 23, Iss 2, Pp 485-

    2018  Volume 498

    Abstract: Summary: Focal adhesions anchor cells to extracellular matrix (ECM) and direct assembly of a pre-stressed actin cytoskeleton. They act as a cellular sensor and regulator, linking ECM to the nucleus. Here, we identify proteolytic turnover of the anti- ... ...

    Abstract Summary: Focal adhesions anchor cells to extracellular matrix (ECM) and direct assembly of a pre-stressed actin cytoskeleton. They act as a cellular sensor and regulator, linking ECM to the nucleus. Here, we identify proteolytic turnover of the anti-adhesive proteoglycan versican as a requirement for maintenance of smooth muscle cell (SMC) focal adhesions. Using conditional deletion in mice, we show that ADAMTS9, a secreted metalloprotease, is required for myometrial activation during late gestation and for parturition. Through knockdown of ADAMTS9 in uterine SMC, and manipulation of pericellular versican via knockdown or proteolysis, we demonstrate that regulated pericellular matrix dynamics is essential for focal adhesion maintenance. By influencing focal adhesion formation, pericellular versican acts upstream of cytoskeletal assembly and SMC differentiation. Thus, pericellular versican proteolysis by ADAMTS9 balances pro- and anti-adhesive forces to maintain an SMC phenotype, providing a concrete example of the dynamic reciprocity of cells and their ECM. : Mead et al. identify a proteolytic mechanism that actively maintains a pericellular microenvironment conducive to uterine smooth muscle activation prior to parturition. They show that pericellular matrix proteolysis by the secreted metalloprotease ADAMTS9 is crucial for maintenance of focal adhesions in uterine smooth muscle cells, and its absence impairs parturition. Keywords: metalloprotease, extracellular matrix, smooth muscle, proteoglycan, myometrium, parturition, uterus, focal adhesion, proteolysis, interference reflection microscopy
    Keywords Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2018-04-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6

    Bram P. Prins / Timothy J. Mead / Jennifer A. Brody / Gardar Sveinbjornsson / Ioanna Ntalla / Nathan A. Bihlmeyer / Marten van den Berg / Jette Bork-Jensen / Stefania Cappellani / Stefan Van Duijvenboden / Nikolai T. Klena / George C. Gabriel / Xiaoqin Liu / Cagri Gulec / Niels Grarup / Jeffrey Haessler / Leanne M. Hall / Annamaria Iorio / Aaron Isaacs /
    Ruifang Li-Gao / Honghuang Lin / Ching-Ti Liu / Leo-Pekka Lyytikäinen / Jonathan Marten / Hao Mei / Martina Müller-Nurasyid / Michele Orini / Sandosh Padmanabhan / Farid Radmanesh / Julia Ramirez / Antonietta Robino / Molly Schwartz / Jessica van Setten / Albert V. Smith / Niek Verweij / Helen R. Warren / Stefan Weiss / Alvaro Alonso / David O. Arnar / Michiel L. Bots / Rudolf A. de Boer / Anna F. Dominiczak / Mark Eijgelsheim / Patrick T. Ellinor / Xiuqing Guo / Stephan B. Felix / Tamara B. Harris / Caroline Hayward / Susan R. Heckbert / Paul L. Huang

    Genome Biology, Vol 19, Iss 1, Pp 1-

    2018  Volume 17

    Abstract: Abstract Background Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants ... ...

    Abstract Abstract Background Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. Results Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. Conclusions Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.
    Keywords Exome chip ; Conduction ; ADAMTS6 ; Meta-analysis ; Biology (General) ; QH301-705.5 ; Genetics ; QH426-470
    Subject code 572
    Language English
    Publishing date 2018-07-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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