Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-β receptor I internalization and inhibiting transforming growth factor-β1 signaling

Am J Respir Crit Care Med. 2013 Oct 1;188(7):831-41. doi: 10.1164/rccm.201303-0434OC.

Abstract

Rationale: Alveolar transforming growth factor (TGF)-β1 signaling and expression of TGF-β1 target genes are increased in patients with idiopathic pulmonary fibrosis (IPF) and in animal models of pulmonary fibrosis. Internalization and degradation of TGF-β receptor TβRI inhibits TGF-β signaling and could attenuate development of experimental lung fibrosis.

Objectives: To demonstrate that after experimental lung injury, human syndecan-2 confers antifibrotic effects by inhibiting TGF-β1 signaling in alveolar epithelial cells.

Methods: Microarray assays were performed to identify genes differentially expressed in alveolar macrophages of patients with IPF versus control subjects. Transgenic mice that constitutively overexpress human syndecan-2 in macrophages were developed to test the antifibrotic properties of syndecan-2. In vitro assays were performed to determine syndecan-2-dependent changes in epithelial cell TGF-β1 signaling, TGF-β1, and TβRI internalization and apoptosis. Wild-type mice were treated with recombinant human syndecan-2 during the fibrotic phase of bleomycin-induced lung injury.

Measurements and main results: We observed significant increases in alveolar macrophage syndecan-2 levels in patients with IPF. Macrophage-specific overexpression of human syndecan-2 in transgenic mice conferred antifibrotic effects after lung injury by inhibiting TGF-β1 signaling and downstream expression of TGF-β1 target genes, reducing extracellular matrix production and alveolar epithelial cell apoptosis. In vitro, syndecan-2 promoted caveolin-1-dependent internalization of TGF-β1 and TβRI in alveolar epithelial cells, which inhibited TGF-β1 signaling and epithelial cell apoptosis. Therapeutic administration of human syndecan-2 abrogated lung fibrosis in mice.

Conclusions: Alveolar macrophage syndecan-2 exerts antifibrotic effects by promoting caveolin-1-dependent TGF-β1 and TβRI internalization and inhibiting TGF-β1 signaling in alveolar epithelial cells. Hence, molecules that facilitate TβRI degradation via endocytosis represent potential therapies for pulmonary fibrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Bleomycin / administration & dosage
  • Bronchoalveolar Lavage
  • Caveolin 1 / drug effects
  • Disease Models, Animal
  • Gene Expression Profiling
  • Genetic Markers
  • Humans
  • Hydroxyproline / analysis
  • Idiopathic Pulmonary Fibrosis / chemically induced*
  • Idiopathic Pulmonary Fibrosis / drug therapy
  • Idiopathic Pulmonary Fibrosis / genetics
  • In Vitro Techniques
  • Macrophages, Alveolar / drug effects*
  • Mice
  • Mice, Transgenic
  • Signal Transduction
  • Syndecan-2 / physiology
  • Syndecan-2 / therapeutic use*
  • Tissue Array Analysis
  • Transforming Growth Factor beta1 / drug effects*
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / physiology
  • Up-Regulation / drug effects
  • Up-Regulation / physiology

Substances

  • Caveolin 1
  • Genetic Markers
  • Transforming Growth Factor beta1
  • Bleomycin
  • Syndecan-2
  • Hydroxyproline