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Open AccessArticle

Syndecan-4 Inhibits the Development of Pulmonary Fibrosis by Attenuating TGF-β Signaling

Department of Pulmonary Medicine, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan
The Center of Lung Biology, University of Washington School of Medicine, 850 Republican St, Seattle, WA 98109, USA
Department of Pathology, Asahikawa Medical University Hospital, Midorigaoka-Higashi 2-1-1, Asahikawa, Hokkaido 078-8510, Japan
Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, 1-1-20 Daiko-Minami, Higashi-ku, Nagoya, Aichi 461-8673, Japan
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(20), 4989;
Received: 23 September 2019 / Accepted: 4 October 2019 / Published: 9 October 2019
(This article belongs to the Special Issue TGF-Beta Super Family Signaling 2.0)
Syndecan-4 is a transmembrane heparan sulfate proteoglycan expressed in a variety of cells, and its heparan sulfate glycosaminoglycan side chains bind to several proteins exhibiting various biological roles. The authors have previously demonstrated syndecan-4′s critical roles in pulmonary inflammation. In the current study, however, its role in pulmonary fibrosis was evaluated. Wild-type and syndecan-4-deficient mice were injected with bleomycin, and several parameters of inflammation and fibrosis were analyzed. The mRNA expression of collagen and α-smooth muscle action (α-SMA) in lung tissues, as well as the histopathological lung fibrosis score and collagen content in lung tissues, were significantly higher in the syndecan-4-deficient mice. However, the total cell count and cell differentiation in bronchoalveolar lavage fluid were equivalent between the wild-type and syndecan-4-deficient mice. Although there was no difference in the TGF-β expression in lung tissues between the wild-type and syndecan-4-deficient mice, significantly more activation of Smad3 in lung tissues was observed in the syndecan-4-deficient mice compared to the wild-type mice. Furthermore, in the in vitro experiments using lung fibroblasts, the co-incubation of syndecan-4 significantly inhibited TGF-β-induced Smad3 activation, collagen and α-SMA upregulation. Moreover, syndecan-4 knock-down by siRNA increased TGF-β-induced Smad3 activation and upregulated collagen and α-SMA expression. These findings showed that syndecan-4 inhibits the development of pulmonary fibrosis, at least in part, through attenuating TGF-β signaling. View Full-Text
Keywords: syndecan-4; pulmonary fibrosis; TGF-β; fibroblasts; proteoglycan syndecan-4; pulmonary fibrosis; TGF-β; fibroblasts; proteoglycan
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Tanino, Y.; Wang, X.; Nikaido, T.; Misa, K.; Sato, Y.; Togawa, R.; Kawamata, T.; Kikuchi, M.; Frevert, C.W.; Tanino, M.; Kojima, T.; Shibata, Y. Syndecan-4 Inhibits the Development of Pulmonary Fibrosis by Attenuating TGF-β Signaling. Int. J. Mol. Sci. 2019, 20, 4989.

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