A common signaling pathway unites diverse fibrotic diseases in humans, Stanford researchers have found. An antibody called anti–CD47, which is being tested as an anti–cancer agent, reverses fibrosis in mice.

Researchers at the Stanford University School of Medicine have identified a pathway that, when mutated, drives fibrosis in many organs of the body.

The pathway underlies what have been considered somewhat disparate conditions, including scleroderma, idiopathic pulmonary fibrosis, liver cirrhosis, kidney fibrosis and more, the researchers found. These diseases are often incurable and life–threatening.

Importantly, the researchers were able to reverse lung fibrosis in mice by administering an antibody called anti–CD47 now being tested as an anti–cancer treatment. “The variety of diseases caused by overproduction of fibroblasts has made finding a common root cause very challenging, in part because there has been no good animal model of these conditions,” said Irving Weissman, MD, professor of pathology and of developmental biology. “Now we’ve shown that activating a single signaling pathway in mice causes fibrosis in nearly all tissues. Blocking the CD–47 signal, which protects cancer cells from the immune system, can also ameliorate these fibrotic diseases even in the most extreme cases.”

The researchers hope their findings will lead to the development of a reliable treatment of many types of fibrotic diseases. They are also planning to investigate whether the anti–CD47 antibody could be an effective treatment for people with fibrosis.

A study describing the research was published online April 17 in the Proceedings of the National Academy of Sciences. Weissman, who directs Stanford’s Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Center for Cancer Stem Cell Research and Medicine, is the senior author. Gerlinde Wernig, MD, assistant professor of pathology, is the lead author.

Fibrosis occurs when the body’s normal response to injury goes astray. An overenthusiastic or inappropriately timed proliferation of cells called fibroblasts, which make up the connective tissue surrounding and supporting all of our organs, can lead to many devastating diseases. Until now, it’s not been clear whether these diseases share a common biological pathway.

The researchers were building upon previous work by Wernig on a condition called myelofibrosis, or fibrosis of the bone marrow. In a mouse model she developed, she had found that fibroblasts were producing unusually high levels of an important signaling molecule called c–Jun. C–Jun is a transcription factor that drives the production of many proteins involved in critical cellular processes. It’s been implicated in many types of human cancer.

In the current study, Wernig investigated c–Jun expression levels in 454 biopsied tissue samples from patients with a variety of fibrotic diseases. She found that in every case the fibroblasts from the patients with fibrosis expressed higher levels of c–Jun than did control fibroblasts collected from people with nonfibrotic conditions.

“We found that c–Jun is not just over–expressed, but it’s also highly activated,” Wernig said. “We wondered if its activity is necessary to maintain the disease.”

Blocking the expression of c–Jun in laboratory–grown lung fibroblasts collected from people with idiopathic pulmonary fibrosis substantially decreased the proliferation of these cells, but not of lung fibroblasts collected from people without fibrosis, Wernig said. Furthermore, mice genetically engineered to overexpress c–Jun in all their body’s tissues developed fibrosis in nearly every organ, including lung, liver, skin and bone marrow. Finally, she also found an intriguing link to past work from the Weissman lab.