DACT2 Protein at High Levels Eases Lung Scarring in IPF Mouse Models

More of DACT2 seen to limit energy in fibrosis-driving myofibroblast cells

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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A protein called DACT2 alleviated signs of lung scarring in mouse models of idiopathic pulmonary fibrosis (IPF), researchers reported.

In tests in cells, DACT2 was found to work by suppressing glycolysis, an energy-producing metabolic process that is overactive in myofibroblasts, the cells involved in excess scar tissue formation in IPF.

According to researchers, these findings support DACT2’s potential as a pharmacological target for IPF treatments.

The study, “DACT2 protects against pulmonary fibrosis via suppressing glycolysis in lung myofibroblasts,” was published in the International Journal of Biological Macromolecules.

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Protein known to have essential roles in tissue injury and repair

Myofibroblasts produce components of the extracellular matrix (ECM), including the protein collagen that surrounds and supports cells, and they play a role in tissue repair. In IPF, these cells produce too much ECM, leading to excessive tissue scarring in the lungs and making it difficult for patients to breathe.

DACT2 is a protein with essential roles in tissue injury and repair. However, its role in IPF remains largely unknown.

“We aimed to investigate the role of DACT2 in the development of pulmonary fibrosis and the therapeutic potential of targeting DACT2 related signaling pathways,” the researchers wrote.

Lung fibrosis was induced in mice using the chemical bleomycin, which led to a marked decrease in DACT2 levels compared with healthy control mice.

Ten days after IPF induction, the lung of some mice were exposed to a harmless virus that carried genetic instructions to overproduce DACT2, and others to a blank control virus.

In lung tissues from DACT2-treated mice, markers for fibrosis, including collagen, alpha-SMA, and hydroxyproline, were significantly lower compared with untreated IPF mice.

To validate these results, the team showed that DACT2 overproduction also eased the severity of lung fibrosis in another IPF mouse model induced by exposure to TGF-beta, a signaling protein that drives myofibroblast growth and the deposition of scar tissue in pulmonary fibrosis.

Together, these results suggested that “DACT2 exerted therapeutic effects on bleomycin-induced pulmonary fibrosis in vivo,” meaning in the live animals, the team wrote.

TGF-beta stimulates fibroblasts — the most common cell type found in connective tissue — to transform, or differentiate, into myofibroblasts.

In a human fibroblast cell line, the production of DACT2 dropped in response to TGF-beta stimulation. In contrast, DACT2 overproduction suppressed TGF-beta signaling and, at the same time, blocked increased production of collagen and alpha-SMA. Similar results were seen using a mouse fibroblast cell line.

Work supports further pulmonary fibrosis research into DACT2

Emerging evidence suggests that glycolysis — the metabolic process that converts glucose (blood sugar) into chemical energy to provide power to cells — is the major metabolic pathway in lung myofibroblasts during IPF progression.

TGF-beta stimulation led to a significant increase in glucose uptake in cells and intracellular levels of ATP, the chemical energy molecule generated by glucose metabolism. These results confirmed the “enhancement of glycolysis in lung myofibroblasts,” the team wrote.

Greater DACT2 production suppressed glycolysis in lung myofibroblasts. It also lowered the levels of lactate, a metabolite of glycolysis, both inside and outside cells.

Lower lactate levels were explained by a drop in the levels of LDHA, the enzyme that generates lactate, in response to DACT2, “indicating that DACT2 may inhibit the fibrotic [features] of lung fibroblasts possibly by regulating LDHA,” the researchers wrote.

These findings were confirmed by overproducing LDHA, which prevented the DACT2-mediated suppression of fibrosis markers, and demonstrated that “DACT2 inhibited lung myofibroblast differentiation by downregulating LDHA.”

Finally, the team showed DACT2 lowered LDHA levels by enhancing its degradation in lysosomes, the structures within cells where damaged or unnecessary molecules are broken down and recycled.

“These results provide evidence for the beneficial role of DACT2 in pulmonary fibrosis and other chronic lung disorders,” the scientists wrote, suggesting “DACT2 might be a novel target for IPF treatments.”

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