Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Dysregulated overexpression of Sox9 induces fibroblast activation in pulmonary fibrosis
Prathibha R. Gajjala, … , Anil G. Jegga, Satish K. Madala
Prathibha R. Gajjala, … , Anil G. Jegga, Satish K. Madala
Published September 14, 2021
Citation Information: JCI Insight. 2021;6(20):e152503. https://doi.org/10.1172/jci.insight.152503.
View: Text | PDF
Research Article Pulmonology

Dysregulated overexpression of Sox9 induces fibroblast activation in pulmonary fibrosis

  • Text
  • PDF
Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease associated with unremitting fibroblast activation including fibroblast-to-myofibroblast transformation (FMT), migration, resistance to apoptotic clearance, and excessive deposition of extracellular matrix (ECM) proteins in the distal lung parenchyma. Aberrant activation of lung-developmental pathways is associated with severe fibrotic lung disease; however, the mechanisms through which these pathways activate fibroblasts in IPF remain unclear. Sry-box transcription factor 9 (Sox9) is a member of the high-mobility group box family of DNA-binding transcription factors that are selectively expressed by epithelial cell progenitors to modulate branching morphogenesis during lung development. We demonstrate that Sox9 is upregulated via MAPK/PI3K-dependent signaling and by the transcription factor Wilms’ tumor 1 in distal lung-resident fibroblasts in IPF. Mechanistically, using fibroblast activation assays, we demonstrate that Sox9 functions as a positive regulator of FMT, migration, survival, and ECM production. Importantly, our in vivo studies demonstrate that fibroblast-specific deletion of Sox9 is sufficient to attenuate collagen deposition and improve lung function during TGF-α–induced pulmonary fibrosis. Using a mouse model of bleomycin-induced pulmonary fibrosis, we show that myofibroblast-specific Sox9 overexpression augments fibroblast activation and pulmonary fibrosis. Thus, Sox9 functions as a profibrotic transcription factor in activating fibroblasts, illustrating the potential utility of targeting Sox9 in IPF treatment.

Authors

Prathibha R. Gajjala, Rajesh K. Kasam, Divyalakshmi Soundararajan, Debora Sinner, Steven K. Huang, Anil G. Jegga, Satish K. Madala

×

Figure 1

SOX9 is upregulated in the distal lung fibroblasts during the pathogenesis of pulmonary fibrosis.

Options: View larger image (or click on image) Download as PowerPoint
SOX9 is upregulated in the distal lung fibroblasts during the pathogenes...
(A) Quantification of SOX9 transcripts from the total lung RNA of healthy individuals and patients with IPF by real-time PCR (RT-PCR). (*P < 0.05; n = 5–6/group; Student’s 2-tailed t test.) (B) Immunostaining was performed with the anti-SOX9 antibody on lung sections of normal individuals and patients with IPF. Representative images were obtained at 40× original magnification. Scale bar: 150 μm (n = 5/group). (C) Quantification of SOX9-positive cells normalized to the total lung cells in images of lung sections from normal individuals and patients with IPF was performed using a BZ-X analyzer. (****P < 0.00005; n = 5/group; Student’s 2-tailed t test.) (D) Quantification of SOX9 transcripts in primary lung fibroblasts grown from normal and IPF lungs by RT-PCR. (**P < 0.005; n = 4/group; Student’s 2-tailed t test.) (E) Confocal microscopy images of lung sections from normal individuals and patients with IPF stained with anti-SOX9 (green color) and anti-vimentin (red color) antibodies and nuclei stained with DAPI (blue color). Cells positive for both SOX9 and vimentin are highlighted with white arrows. Images obtained at 60× original magnification. Scale bar: 50 μm (n = 5/group). (F) Quantification of Sox9 transcripts in the total lung transcripts of TGFαOE mice treated with Dox for 0, 1, 4, 14, and 28 days (****P < 0.00005; n = 4–5/group; 1-way ANOVA). (G) Confocal images of lung sections from control and TGFαOE mice stained with anti-SOX9 (green color) and anti-ACTA2 (red color) or anti-vimentin (red color) antibodies and nuclei stained with DAPI (blue color). Scale bar: 50 μm (n = 5/group). (H) Primary lung-resident fibroblasts isolated from lung cultures of control and TGFαOE mice treated with Dox for 4 weeks were immunoblotted with antibodies against SOX9 and GAPDH. SOX9 protein levels were normalized to GAPDH and are shown as fold induced change using a bar graph (**P < 0.005, n = 3/group; Student’s 2-tailed t test).

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts