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

Liu, G; Cooley, MA; Jarnicki, AG; Borghuis, T; Nair, PM; Tjin, G; Hsu, AC; Haw, TJ; Fricker, M; Harrison, CL; Jones, B; Hansbro, NG; Wark, PA; Horvat, JC; Scott Argraves, W; Oliver, BG; Knight, DA; Burgess, JK; Hansbro, PM

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

Cooley, MA Jarnicki, AG Borghuis, T Nair, PM Tjin, G Hsu, AC Haw, TJ Fricker, M Harrison, CL Jones, B Hansbro, NG Wark, PA Horvat, JC Scott Argraves, W Oliver, BG

Knight, DA Burgess, JK Hansbro, PM

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Publication Type:: Journal Article
Citation:: JCI Insight, 2019, 4 (16)
Issue Date:: 2019-07-25

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Field	Value	Language
dc.contributor.author	Liu, G https://orcid.org/0000-0002-0489-2638	en_US
dc.contributor.author	Cooley, MA	en_US
dc.contributor.author	Jarnicki, AG	en_US
dc.contributor.author	Borghuis, T	en_US
dc.contributor.author	Nair, PM	en_US
dc.contributor.author	Tjin, G	en_US
dc.contributor.author	Hsu, AC	en_US
dc.contributor.author	Haw, TJ	en_US
dc.contributor.author	Fricker, M	en_US
dc.contributor.author	Harrison, CL	en_US
dc.contributor.author	Jones, B	en_US
dc.contributor.author	Hansbro, NG	en_US
dc.contributor.author	Wark, PA	en_US
dc.contributor.author	Horvat, JC	en_US
dc.contributor.author	Scott Argraves, W	en_US
dc.contributor.author	Oliver, BG https://orcid.org/0000-0002-7122-9262	en_US
dc.contributor.author	Knight, DA	en_US
dc.contributor.author	Burgess, JK	en_US
dc.contributor.author	Hansbro, PM https://orcid.org/0000-0002-4741-3035	en_US
dc.date.issued	2019-07-25	en_US
dc.identifier.citation	JCI Insight, 2019, 4 (16)	en_US
dc.identifier.uri	http://hdl.handle.net/10453/137003
dc.description.abstract	Copyright: © 2019, American Society for Clinical Investigation. 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.	en_US
dc.relation	http://purl.org/au-research/grants/nhmrc/GNT1079187
dc.relation.ispartof	JCI Insight	en_US
dc.relation.isbasedon	10.1172/jci.insight.124529	en_US
dc.title	Fibulin-1c regulates transforming growth factor–β activation in pulmonary tissue fibrosis	en_US
dc.type	Journal Article
utslib.citation.volume	16	en_US
utslib.citation.volume	4	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	1102 Cardiorespiratory Medicine and Haematology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	open_access
pubs.issue	16	en_US
pubs.publication-status	Published	en_US
pubs.volume	4	en_US

Abstract:

Copyright: © 2019, American Society for Clinical Investigation. 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.

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http://hdl.handle.net/10453/137003