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Article

EDA fibronectin–TLR4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis

Alessandro Malara, Cristian Gruppi, View ORCID ProfileVittorio Abbonante, Daniele Cattaneo, View ORCID ProfileLuigi De Marco, Margherita Massa, Alessandra Iurlo, View ORCID ProfileUmberto Gianelli, Carlo L. Balduini, Maria E. Tira, View ORCID ProfileAndrès F. Muro, Anil K. Chauhan, Vittorio Rosti, Giovanni Barosi, View ORCID ProfileAlessandra Balduini  Correspondence email
Alessandro Malara
Department of Molecular Medicine, University of Pavia, Pavia, ItalyLaboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientific San Matteo Foundation, Pavia, Italy
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Cristian Gruppi
Department of Molecular Medicine, University of Pavia, Pavia, Italy
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Vittorio Abbonante
Department of Molecular Medicine, University of Pavia, Pavia, ItalyLaboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientific San Matteo Foundation, Pavia, Italy
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  • ORCID record for Vittorio Abbonante
Daniele Cattaneo
Hematology Division, Istituto di Ricovero e Cura a Carattere Scientific Ca' Granda-Maggiore Policlinico Hospital Foundation, Milan, Italy
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Luigi De Marco
Department of Translational Research, National Cancer Center (Istituto di Ricovero e Cura a Carattere Scientific Centro di Riferimento Oncologico), Aviano, ItalyDepartment of Molecular and Experimental Research, The Scripps Research Institute, La Jolla, CA
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  • ORCID record for Luigi De Marco
Margherita Massa
Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientific San Matteo Foundation, Pavia, Italy
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Alessandra Iurlo
Hematology Division, Istituto di Ricovero e Cura a Carattere Scientific Ca' Granda-Maggiore Policlinico Hospital Foundation, Milan, Italy
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Umberto Gianelli
Division of Pathology, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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  • ORCID record for Umberto Gianelli
Carlo L. Balduini
Department of Internal Medicine, Istituto di Ricovero e Cura a Carattere Scientific San Matteo Foundation, Pavia, Italy
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Maria E. Tira
Department of Biology and Biotechnology “Lazzaro Spallanzani,” University of Pavia, Pavia, Italy
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Andrès F. Muro
The International Center for Genetic Engineering and Biotechnology, Trieste, Italy
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  • ORCID record for Andrès F. Muro
Anil K. Chauhan
Department of Internal Medicine, University of Iowa, Iowa City, IA
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Vittorio Rosti
Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientific Policlinico S. Matteo Foundation, Pavia, Italy
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Giovanni Barosi
Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientific Policlinico S. Matteo Foundation, Pavia, Italy
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Alessandra Balduini
Department of Molecular Medicine, University of Pavia, Pavia, ItalyLaboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientific San Matteo Foundation, Pavia, ItalyDepartment of Biomedical Engineering, Tufts University, Medford, MA
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  • ORCID record for Alessandra Balduini
  • For correspondence: alessandra.balduini@tufts.edu
DOI: 10.1084/jem.20181074 | Published February 7, 2019
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Abstract

The fibronectin EDA isoform (EDA FN) is instrumental in fibrogenesis but, to date, its expression and function in bone marrow (BM) fibrosis have not been explored. We found that mice constitutively expressing the EDA domain (EIIIA+/+), but not EDA knockout mice, are more prone to develop BM fibrosis upon treatment with the thrombopoietin (TPO) mimetic romiplostim (TPOhigh). Mechanistically, EDA FN binds to TLR4 and sustains progenitor cell proliferation and megakaryopoiesis in a TPO-independent fashion, inducing LPS-like responses, such as NF-κB activation and release of profibrotic IL-6. Pharmacological inhibition of TLR4 or TLR4 deletion in TPOhigh mice abrogated Mk hyperplasia, BM fibrosis, IL-6 release, extramedullary hematopoiesis, and splenomegaly. Finally, developing a novel ELISA assay, we analyzed samples from patients affected by primary myelofibrosis (PMF), a well-known pathological situation caused by altered TPO signaling, and found that the EDA FN is increased in plasma and BM biopsies of PMF patients as compared with healthy controls, correlating with fibrotic phase.

  • Submitted: 7 June 2018
  • Revision received 26 November 2018
  • Accepted: 9 January 2019
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This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

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© 2019 Malara et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

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EDA fibronectin–TLR4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis
Alessandro Malara, Cristian Gruppi, Vittorio Abbonante, Daniele Cattaneo, Luigi De Marco, Margherita Massa, Alessandra Iurlo, Umberto Gianelli, Carlo L. Balduini, Maria E. Tira, Andrès F. Muro, Anil K. Chauhan, Vittorio Rosti, Giovanni Barosi, Alessandra Balduini
Journal of Experimental Medicine Feb 2019, jem.20181074; DOI: 10.1084/jem.20181074

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The Journal of Experimental Medicine: 216 (2)

Current Issue

February 4, 2019
Volume 216, No. 2

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