Dysregulated overexpression of Sox9 induces fibroblast activation in pulmonary fibrosis

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

doi:10.1172/jci.insight.152503

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.

Highlights

Pulmonary fibrosis is the final common pathway of several lung diseases caused by dysregulated healing responses to chronic lung injury
We showed that SOX9 was aberrantly activated in fibroblasts of distal lung fibrotic lesions in both human Idiopathic pulmonary fibrosis (IPF) and a mouse model of TGF-α–induced pulmonary fibrosis
We demonstrated that the TGF-α/Wilms’ tumor 1 (WT1) axis was involved in SOX9 upregulation in pulmonary fibrosis

Summary

Introduction

Pulmonary fibrosis is the final common pathway of several lung diseases caused by dysregulated healing responses to chronic lung injury. Idiopathic pulmonary fibrosis (IPF) is perhaps the most severe and enigmatic form of interstitial lung disease, and recent epidemiological studies suggest that the prevalence of the disease is increasing in the United States and globally. The mortality rate of IPF is increasing every year as well, and the disease is one of the leading causes of death among the aging population [2]. The survival rate after diagnosis is typically 3 to 5 years, which is partly due to a lack of effective treatments or cure. The major impediment to developing new therapies is the lack of knowledge regarding mechanisms underlying fibroblast activation in IPF.

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