Hippo signaling pathway provides new insight into systemic sclerosis

Systemic sclerosis causes tightening and hardening of the skin, leading to a life-threatening autoimmune disease associated with pulmonary fibrosis and kidney disease.

Health researchers at the University of Michigan have studied the pathology of systemic sclerosis to better understand the disease and identify key pathways in the disease process that can be targeted therapeutically. Now, a research team led by University of Michigan Health’s Dinesh Khanna, MBBS, M.Sc., professor of rheumatology, and Johann Gudjonsson, MD, Ph.D., professor of dermatology, in collaboration with John Varga, MD , professor and chief of rheumatology, characterized the major cellular sources of fibrosis in the skin of patients with cutaneous systemic sclerosis, identifying myofibroblasts and a subset of endothelial cells as major contributors.

The work is published in the journal Natural communications.

The research examined the Hippo signaling pathway, an evolutionarily conserved signaling pathway that plays a complex role in cellular function as a major pathway promoting fibrosis in systemic sclerosis. By directly targeting the Hippo signaling pathway, the research team demonstrated a reversal of pro-fibrotic responses in myofibroblasts and endothelial cells.

The discovery of this function of the Hippo signaling pathway in systemic sclerosis is linked to previous work that identified a regulator of this pathway as a key factor in sex-biased immune responses, providing evidence that may help explain why the Systemic sclerosis is much more common in women. only men.

The results reported in this article showed a marked effect of the drug verteporfin, which targets the Hippo signaling pathway, and a rapid reversal of the pro-fibrotic phenotype in myofibroblasts and endothelial cells.

“Verteporfin is approved for the treatment of a subtype of macular degeneration, suggesting that it could be repurposed to treat systemic sclerosis,” Gudjonsson said. “This work helps shift the focus to a new pathway that is a key driver of key features seen in systemic sclerosis and has the potential to move quickly to testing in clinical trials.”

Additionally, the researchers believe that the unique and comprehensive nature of the data generated in this project could become valuable to other researchers studying systemic sclerosis.

“This is something Khanna and I aim to create a proof-of-concept trial in the near future to test this theory and other advances in the treatment and care of systemic sclerosis,” said Gudjonsson.

Other authors include Feiyang Ma Pei-Suen Tsou, Danielle Ochocki, Mehrnaz Gharaee-Kermani, Olesya Plazyo, Xianying Xing, Joseph Kirma, Rachael Wasikowski, William D. Brodie, J. Michelle Kahlenberg, and Allison C. Billi.