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

Abstract

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.

• Authors: Yoshinori Tanino, Xintao Wang, Takefumi Nikaido, Kenichi Misa, Yuki Sato, Ryuichi Togawa, Takaya Kawamata, Masami Kikuchi, Charles W Frevert, Mishie Tanino, Tetsuhito Kojima, Yoko Shibata
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 20 Issue 20 (Oct 09 2019) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 31600983 (Publication Type: Journal Article)

Chemical References

• Actins
• Syndecan-4
• Transforming Growth Factor beta
• alpha-smooth muscle actin, mouse
• Collagen

Topics

• Actins (metabolism)
• Animals
• Collagen (metabolism)
• Disease Models, Animal
• Fibroblasts (metabolism)
• Lung (metabolism, pathology)
• Mice
• Mice, Knockout
• Pulmonary Fibrosis (etiology, metabolism, pathology)
• Signal Transduction
• Syndecan-4 (genetics, metabolism)
• Transforming Growth Factor beta (metabolism)