Runx2 protein may be treatment target for pulmonary fibrosis
Runx2 plays key role in converting healthy fibroblasts into fibrosis-driving cells
A protein called Runx2 contributes to the abnormal activity of lung cells that drive pulmonary fibrosis, a new study shows, suggesting that inhibiting this protein may be an effective strategy for treating the disease.
“Our study suggests Runx2 is a potential therapeutic target for preventing or treating pulmonary fibrosis and gives researchers a platform to find even more opportunities to prevent the aggressive progression of this disease,” Jianwen Que, MD, PhD, a professor at Columbia University and one of the study’s corresponding authors, said in a university news story.
The study, “RUNX2 promotes fibrosis via an alveolar-to-pathological fibroblast transition,” was published in Nature.
Pulmonary fibrosis is marked by the buildup of scar tissue in the lungs. Excessive scar tissue in the lungs makes it harder for the lungs to inflate with air and take in oxygen, ultimately causing symptoms like shortness of breath.
Scar tissue in the lungs and other parts of the body is produced mainly by specialized cells called fibroblasts. Normally, fibroblasts become active to help repair damaged tissues and heal wounds. However, in pulmonary fibrosis, these cells start to make too much scar tissue, ultimately driving the disease.
‘These cells are trying to repair lung injuries, but they go too far’
“Ironically, these cells are trying to repair lung injuries, but they go too far,” Que said. “The scar tissue they produce increasingly encases the lung’s air sacs in a stiff matrix. The lung literally becomes too hard to breathe.”
Pathological, or disease-driving, fibroblasts play a key role in the initiation and progression of pulmonary fibrosis, but where these abnormal cells come from has been a mystery.
“Not knowing the sources of these pathological cells has really hampered the development of therapies that could put a stop to this disease, so there’s been an intense effort to find them,” Que said.
Using mouse models, the researchers conducted detailed analyses of cellular lineage to pinpoint the origin of the pathological fibroblasts driving pulmonary fibrosis.
The team found that, during the normal development of the lungs, there’s a specific population of fibroblasts in the alveoli, or the tiny air sacs in the lungs where gas exchange occurs, that express, or produce, a protein called leptin receptor (LEPR). Data indicate that, in disease conditions, these LEPR-expressing cells can transform into pathological fibroblasts.
“After injury, LEPR[-positive] cell derivatives, the majority of which are alveolar fibroblasts, differentiated into … pathological fibroblasts,” the researchers wrote.
Blocking Runx2 prevented fibroblasts from turning into pathological ones
Further investigation revealed a protein called Runx2 plays a central role in the transition from healthy to disease-driving fibroblasts. Runx2 is a transcription factor, a type of protein that helps control the activity of certain genes inside cells. The researchers found that when they inactivated the gene encoding Runx2, healthy fibroblasts didn’t transition into pathological ones. Inactivating this gene also reduced the amount of scar tissue in the lungs of mice.
Runx2 “is a key driver for pulmonary fibrosis, and inactivation of [the RUNX2 gene] blocked the transition of alveolar fibroblasts to pathological fibroblasts,” the scientists wrote.
These data suggest blocking Runx2 might be a useful therapeutic strategy, as it could theoretically stop the formation of disease-driving cells. The scientists noted more work will be needed to develop treatment strategies targeting this protein.
“It may take years to translate our findings, but we hope they will lead to more effective treatments,” Que said.
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