The matricellular protein CCN1 enhances TGF‐β1/SMAD3‐dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury

ABSTRACT Matricellular proteins mediate pleiotropic effects during tissue injury and repair. CCN1 is a matricellular protein that has been implicated in angiogenesis, inflammation, and wound repair. In this study, we identified CCN1 as a gene that is differentially up‐regulated in alveolar mesenchym...

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Bibliographic Details
Published in:The FASEB journal 2016-06, Vol.30 (6), p.2135-2150
Main Authors: Kurundkar, Ashish R., Kurundkar, Deepali, Rangarajan, Sunad, Locy, Morgan L., Zhou, Yong, Liu, Rui‐Ming, Zmijewski, Jaroslaw, Thannickal, Victor J.
Format: Article
Language:English
Subjects:
Animals
Cells, Cultured
Cysteine-Rich Protein 61 - genetics
Cysteine-Rich Protein 61 - metabolism
Fibroblasts - metabolism
Gene Expression Regulation - physiology
Gene Knockdown Techniques
Humans
idiopathic pulmonary fibrosis
Lung Injury - metabolism
matrix remodeling
myofibroblasts
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Pulmonary Fibrosis - metabolism
Receptor, Transforming Growth Factor-beta Type I
Receptors, Transforming Growth Factor beta - genetics
Receptors, Transforming Growth Factor beta - metabolism
RNA Interference
Signal Transduction - physiology
Smad3 Protein - genetics
Smad3 Protein - metabolism
Transforming Growth Factor beta1 - genetics
Transforming Growth Factor beta1 - metabolism
Up-Regulation
wound repair
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Summary:ABSTRACT Matricellular proteins mediate pleiotropic effects during tissue injury and repair. CCN1 is a matricellular protein that has been implicated in angiogenesis, inflammation, and wound repair. In this study, we identified CCN1 as a gene that is differentially up‐regulated in alveolar mesenchymal cells of human subjects with rapidly progressive idiopathic pulmonary fibrosis (IPF). Elevated levels of CCN1 mRNA were confirmed in lung tissues of IPF subjects undergoing lung transplantation, and CCN1 protein was predominantly localized to fibroblastic foci. CCN1 expression in ex vivo IPF lung fibroblasts correlated with gene expression of the extracellular matrix proteins, collagen (Col)1a1, Col1a2, and fibronectin as well as the myofibroblast marker, α‐smooth muscle actin. RNA interference (RNAi)‐mediated knockdown of CCN1 down‐regulated the constitutive expression of these profibrotic genes in IPF fibroblasts. TGF‐β1, a known mediator of tissue fibrogenesis, induces gene and protein expression of CCN1 via a mothers against decapentaplegic homolog 3 (SMAD3)‐dependent mechanism. Importantly, endogenous CCN1 potentiates TGF‐β1‐induced SMAD3 activation and induction of profibrotic genes, supporting a positive feedback loop leading to myofibroblast activation. In vivo RNAi‐mediated silencing of CCN1 attenuates fibrogenic responses to bleomycin‐induced lung injury. These studies support previously unrecognized, cooperative interaction between the CCN1 matricellular protein and canonical TGF‐β1/SMAD3 signaling that promotes lung fibrosis.—Kurundkar, A. R., Kurundkar, D., Rangarajan, S., Locy, M. L., Zhou, Y., Liu, R.‐M., Zmijewski, J., Thannickal, V. J. The matricellular protein CCN1 enhances TGF‐β1/SMAD3‐dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury. FASEB J. 30, 2135–2150 (2016). www.fasebj.org
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.201500173