Dysregulated overexpression of Sox9 induces fibroblast activation in pulmonary fibrosis

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.Sox9 is a member of the HMG 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/PI3Kdependent 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 TGFαinduced 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.

Activin B, a new player in kidney fibrosis?†

“…These data are in keeping with reports supporting a role for Sox9 in fibrosis in other organs including the liver [5] and lung [6]. Interestingly, while previously thought to be expressed only in epithelial cells, Sox9 expression was also recently shown in lung fibroblasts, where it promoted their activation and matrix protein production [6]. This suggests that the importance of this axis to fibrosis may be more generalizable, although Sox9 likely has INHBB-independent profibrotic effects through its role in regulation of other genes.…”

“…Importantly, Sox9 overexpression in cultured epithelial cells increased INHBB, while its downregulation with shRNA prevented INHBB expression in both cultured cells and UUO mice. These data are in keeping with reports supporting a role for Sox9 in fibrosis in other organs including the liver [5] and lung [6]. Interestingly, while previously thought to be expressed only in epithelial cells, Sox9 expression was also recently shown in lung fibroblasts, where it promoted their activation and matrix protein production [6].…”

Nanoparticle targeting of de novo profibrotic macrophages mitigates lung fibrosis

“…Our results showed that MANP target CX3CR1 + SiglecF + macrophages localized in the inflammatory and fibrotic niche in vivo. The protection may thus be the result of disruption of signaling interaction between the targeted CX3CR1 + SiglecF + macrophages and dampening of the proximal fibrogenic fibroblasts by counteracting dysregulated transcriptional programs in fibroblasts ( 50 ). Other possibilities could involve the role of CX3CR1 + SiglecF + macrophages in epithelial–mesenchymal transition believed to contribute to lung fibrosis ( 51 ) and the inhibition of NF-κB–mediated profibrotic gene expression induced by CD148 phosphatase in fibroblasts ( 52 ).…”

Current Perspectives on Nucleus Pulposus Fibrosis in Disc Degeneration and Repair

“…NR4A1 was suggested to bind with SP1 to repress TGF-β target genes in rat injury-induced NP fibrosis [ 59 ]. Smad-mediated signaling can crosstalk with non-Smad pathways, such as MAPKs [ 87 ] and Wnt/β-catenin signaling, to regulate fibrotic response [ 88 ]. In IVDs, altered Wnt or MAPK signaling was found to promote cellular senescence, apoptosis, autophagy and inflammatory responses, thereby accelerating the degeneration process [ 89 , 90 ].…”

“…Sox9 is a well-known master transcription factor for chondrogenic induction and NP cell formation [ 91 ]. It is also associated with fibrosis occurrence and severity in the kidneys [ 92 ] and lungs [ 87 ] via TGF-β [ 87 ] and NAV3-YAP1 signaling [ 92 ]. Interestingly, fibrotic matrisome elements appear enriched in the Sox9-expressing region in degenerative NP [ 25 ].…”