Lung Development Molecule Sox9 May Be Potential Target for IPF

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by Marta Figueiredo PhD |

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The levels of Sox9 — a molecule that promotes lung scarring, or fibrosis — are significantly higher in the lungs of both patients and mouse models of idiopathic pulmonary fibrosis (IPF) than in those of their healthy counterparts, a study shows.

Excessive Sox9 levels were found to promote fibroblasts’ maturation into myofibroblasts, migration, and production of scarring-related molecules — all key contributing events for pulmonary fibrosis (PF).

Notably, blocking Sox9’s activity reduced fibroblast maturation and lung fibrosis in a mouse model of IPF, highlighting the potential of such an approach for treating this patient population, according to researchers.

The team said it is “essential to characterize and understand these underlying molecular mechanisms in order to develop new treatments that attenuate fibroblast activation in IPF.”

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The study, “Dysregulated overexpression of Sox9 induces fibroblast activation in pulmonary fibrosis,” was published in the journal JCI Insight.

IPF, a form of PF with no clear cause, is characterized by excessive wound healing that leads to fibrosis and increased stiffness of lung tissue, making it difficult for patients to breathe.

Excessive wound healing is associated with fibroblast activation, or maturation, into myofibroblasts — the main drivers of lung fibrosis that produce excessive amounts of extracellular matrix (ECM) molecules. ECM molecules surround and support cells, but when overly produced, can cause tissue scarring.

Also, in IPF, myofibroblasts are highly motile — capable of motion — and resistant to death, the investigators noted.

“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,” the researchers wrote.

Now, the team, from the Cincinnati Children’s Hospital Medical Center, in Ohio, showed that Sox9, a molecule that regulates the activity of several genes and is involved in tissue branching during lung development, is overly produced in IPF and promotes several pro-fibrotic events, such as fibroblast activation.

First, by analyzing lung tissue from IPF patients and healthy people, the investigators found that Sox9 levels were significantly increased in patients, particularly in fibrotic lesions and fibroblasts. Similar results were obtained in a mouse model of the disease.

Also, SOX9 production was found to be positively regulated by the TGF-alpha/WT1 axis in lab-grown human fibroblasts. Notably, both TGF-alpha and WT1 have been previously implicated in lung fibrosis. Further analysis showed that SOX9 promotes myofibroblast maturation, migration, ECM production, and resistance to death in lab-grown fibroblasts from IPF patients and mouse models.

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Sox9’s pro-fibrotic role was further confirmed in two mouse models of IPF.

Particularly, the deletion of Sox9 specifically in fibroblasts lessened lung fibrosis and improved the animals’ lung function. In addition, Sox9’s overproduction specifically in myofibroblasts increased the levels of pro-fibrotic molecules, such as TGF-beta1, boosted fibroblast activation, and worsened lung fibrosis.

Moreover, data from an independent group of lung samples from 160 IPF patients and 108 healthy individuals showed that SOX9 levels and the activity of several SOX9-regulated ECM genes were significantly increased in the lungs of IPF patients. In addition, higher levels of SOX9 and SOX9-induced ECM molecules were associated with poorer lung function.

These findings highlight “how excessive SOX9 activity in fibroblasts can contribute to the progressive expansion of fibrotic lesions in the lung and that targeting the aberrant activation of SOX9 could be a therapeutic strategy to mitigate ongoing pulmonary fibrosis in IPF,” the researchers wrote.

Nevertheless, they noted that “further work is necessary to determine the impact of SOX9 in other lung cells including epithelial cells [cells that line the airways] during the initiation, maintenance, and resolution of pulmonary fibrosis.”