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

• Published in: International journal of molecular sciences Vol. 20; no. 20; p. 4989
• Main Authors: Tanino, Yoshinori, Wang, Xintao, Nikaido, Takefumi, Misa, Kenichi, Sato, Yuki, Togawa, Ryuichi, Kawamata, Takaya, Kikuchi, Masami, Frevert, Charles W, Tanino, Mishie, Kojima, Tetsuhito, Shibata, Yoko
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 09.10.2019; MDPI
• Subjects: Actins - metabolism; Animals; Bleomycin; Bronchus; Cell differentiation; Chemokines; Collagen; Collagen - metabolism; Differentiation (biology); Disease Models, Animal; Experiments; Fibroblasts; Fibroblasts - metabolism; Fibrosis; Gene expression; Glycosaminoglycans; Growth factors; Heparan sulfate; Inflammation; Lavage; Lung - metabolism; Lung - pathology; Lung diseases; Lungs; Medical prognosis; Mice; Mice, Knockout; Muscles; Neutrophils; Phosphorylation; Pneumonia; Proteins; proteoglycan; Proteoglycans; Pulmonary fibrosis; Pulmonary Fibrosis - etiology; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Roles; Signal Transduction; siRNA; Smad3 protein; Smooth muscle; Syndecan; syndecan-4; Syndecan-4 - genetics; Syndecan-4 - metabolism; tgf-β; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Wound healing; TGF-β; fibroblasts; syndecan-4; pulmonary fibrosis; proteoglycan
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20204989

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.