Localized expression of tenascin in systemic sclerosis-associated pulmonary fibrosis and its regulation by insulin-like growth factor binding protein 3

Arthritis Rheum. 2012 Jan;64(1):272-80. doi: 10.1002/art.30647.


Objective: To determine the role of insulin-like growth factor binding protein 3 (IGFBP-3) in mediating the effects of transforming growth factor β (TGFβ) on tenascin-C (TN-C) production and to assess the levels of TN-C in vivo in patients with systemic sclerosis (SSc)-associated pulmonary fibrosis.

Methods: Human primary lung fibroblasts were stimulated with TGFβ or IGFBP-3 in the presence or absence of specific small interfering RNAs and chemical inhibitors of the signaling cascade. TN-C levels in lung tissue specimens obtained from patients with SSc-associated pulmonary fibrosis were assessed using immunohistochemical analysis and were compared with the levels in specimens obtained from normal donors. TN-C levels were quantified in sera from normal donors and patients with SSc with or without pulmonary fibrosis, using an enzyme-linked immunosorbent assay.

Results: IGFBP-3 mediated the induction of TN-C by TGFβ. Direct induction of TN-C by IGFBP-3 occurred in a p38 MAP kinase-dependent manner. TN-C levels were abundant in lung tissues from patients with SSc and were localized to subepithelial layers of the distal airways. No TN-C was detectable around the proximal airways. Patients with SSc-associated pulmonary fibrosis had significantly higher levels of circulating TN-C compared with SSc patients without pulmonary fibrosis. Longitudinal samples obtained from patients with SSc before and after the onset of pulmonary fibrosis showed increased levels of TN-C after the onset of pulmonary fibrosis.

Conclusion: IGFBP-3, which is overexpressed in fibrotic lungs, induces production of TN-C by subepithelial fibroblasts. The increased lung tissue levels of TN-C parallel the levels detected in the sera of SSc patients with pulmonary fibrosis, suggesting that TN-C may be a useful biomarker for SSc-related pulmonary fibrosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cells, Cultured
  • Culture Media, Conditioned / chemistry
  • Culture Media, Conditioned / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3 / genetics
  • Insulin-Like Growth Factor Binding Protein 3 / pharmacology*
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Pulmonary Fibrosis / complications
  • Pulmonary Fibrosis / metabolism*
  • Pulmonary Fibrosis / pathology
  • RNA Interference
  • RNA, Small Interfering / administration & dosage
  • Recombinant Proteins / pharmacology
  • Scleroderma, Systemic / complications
  • Scleroderma, Systemic / metabolism*
  • Scleroderma, Systemic / pathology
  • Tenascin / analysis
  • Tenascin / metabolism*
  • Transforming Growth Factor beta / pharmacology
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Culture Media, Conditioned
  • Insulin-Like Growth Factor Binding Protein 3
  • RNA, Small Interfering
  • Recombinant Proteins
  • Tenascin
  • Transforming Growth Factor beta
  • p38 Mitogen-Activated Protein Kinases