Fibulin-1c regulates transforming growth factor–β activation in pulmonary tissue fibrosis

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Abstract

Tissue remodeling/fibrosis is a major feature of all fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). It is underpinned by accumulating extracellular matrix (ECM) proteins. Fibulin-1c (Fbln1c) is a matricellular ECM protein associated with lung fibrosis in both humans and mice and stabilizes collagen formation. Here we discovered that Fbln1c was increased in the lung tissues of patients with IPF and experimental bleomycin-induced pulmonary fibrosis. Fbln1c-deficient ( Fbln1c ^–/– ) mice had reduced pulmonary remodeling/fibrosis and improved lung function after bleomycin challenge. Fbln1c interacted with fibronectin, periostin, and tenascin-C in collagen deposits following bleomycin challenge. In a potentially novel mechanism of fibrosis, Fbln1c bound to latent TGF-β–binding protein 1 (LTBP1) to induce TGF-β activation and mediated downstream Smad3 phosphorylation/signaling. This process increased myofibroblast numbers and collagen deposition. Fbln1c and LTBP1 colocalized in lung tissues from patients with IPF. Thus, Fbln1c may be a novel driver of TGF-β–induced fibrosis involving LTBP1 and may be an upstream therapeutic target.

Abstract

Fibulin-1c binds to latent TGF-β binding protein-1 (LTBP1) to induce TGF-β activation and may be a therapeutic target in idiopathic pulmonary fibrosis.

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Author and article information

Contributors

Gang Liu

Marion A. Cooley

Andrew G. Jarnicki

Theo Borghuis

Prema M. Nair

Gavin Tjin

Alan C. Hsu:

ORCID: http://orcid.org/0000-0002-6640-0846

Tatt Jhong Haw:

ORCID: http://orcid.org/0000-0003-2315-7089

Michael Fricker:

ORCID: http://orcid.org/0000-0002-8587-1774

Celeste L. Harrison

Bernadette Jones:

ORCID: http://orcid.org/0000-0003-4613-7865

Nicole G. Hansbro

Peter A. Wark:

ORCID: http://orcid.org/0000-0001-5676-6126

Jay C. Horvat

W. Scott Argraves

Brian G. Oliver:

ORCID: http://orcid.org/0000-0002-7122-9262

Darryl A. Knight:

ORCID: http://orcid.org/0000-0002-4064-6127

Janette K. Burgess:

ORCID: http://orcid.org/0000-0001-9868-9966

Philip M. Hansbro:

ORCID: http://orcid.org/0000-0002-4741-3035

Journal

Journal ID (nlm-ta): JCI Insight

Journal ID (iso-abbrev): JCI Insight

Journal ID (publisher-id): JCI Insight

Title: JCI Insight

Publisher: American Society for Clinical Investigation

ISSN (Electronic): 2379-3708

Publication date Created: 22 August 2019

Publication date PMC-release: 22 August 2019

Volume: 4

Issue: 16

Electronic Location Identifier: e124529

Affiliations

[1 ]Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, and the University of Newcastle, Newcastle, New South Wales, Australia.

[2 ]School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.

[3 ]Centenary Institute, Sydney, New South Wales, Australia.

[4 ]Department of Oral Biology and Diagnostic Sciences, Augusta University, Augusta, Georgia, USA.

[5 ]Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria, Australia.

[6 ]University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Department of Pathology and Medical Biology, Groningen, Netherlands.

[7 ]Woolcock Institute of Medical Research, Discipline of Pharmacology, the University of Sydney, Sydney, New South Wales, Australia.

[8 ]Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, USA.

Author notes

Address correspondence to: Philip M. Hansbro, Building 93, Royal prince Alfred hospital, Missenden Road, Comperdown, NSW 2050 Australia. Phone: 61.2.9565.6248; Email: Philip.Hansbro@ 123456uts.edu.au .

Authorship note: WSA is deceased.