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

Int J Mol Sci. 2019 Oct 9;20(20):4989. doi: 10.3390/ijms20204989.

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.

Keywords: TGF-β; fibroblasts; proteoglycan; pulmonary fibrosis; syndecan-4.

MeSH terms

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

Substances

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