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Hippo pathway linked to systemic sclerosis

Photo by: Maria Sieglinda von Nudeldorf via Wikimedia Commons

Findings from a recent study characterizing the major cellular sources of fibrosis in the skin of patients with systemic sclerosis skin identify myofibroblasts and a subset of endothelial cells as the major contributors to the skin hardening condition.

The findings were published online in Nature Communications (2024; 15, 210).

The research team was led by University of Michigan Health’s professor of rheumatology Dinesh Khanna, MBBS, MSc., and professor of dermatology Johann Gudjonsson, MD, PhD, in collaboration with professor and chief of rheumatology John Varga, MD.

Using systemic sclerosis skin biopsies from a large cohort of patients, the Investigators examined the Hippo signalling pathway as a major pathway promoting fibrosis in systemic sclerosis.

The research team also directly targeted the Hippo signalling pathway and demonstrated a reversal of the pro-fibrotic responses in both myofibroblasts and endothelial cells.

In a press release from the University of Michigan, the authors note the discovery of this function of the Hippo signalling pathway in systemic sclerosis ties back to prior work that identified a regulator of this pathway as a key driver of sex-biased immune responses. They say this provides evidence that may help explain why systemic sclerosis is much more common in women than men.

The findings reported in this paper showed a marked effect from the drug verteporfin, which targets the Hippo signalling pathway, and rapid reversal of the pro-fibrotic phenotype in both myofibroblasts and endothelial cells.

“Verteporfin is approved for treatment of a subtype of macular degeneration suggesting that it could be repurposed towards treating systemic sclerosis,” said Dr. Gudjonsson, in the release.

“This work helps shift the focus towards a novel pathway that is a key driver of the major features observed in systemic sclerosis and has the potential to be able to move quickly to testing in clinical trials.”

Furthermore, the researchers say they believe the unique and comprehensive nature of the data generated in this project may become valuable to other investigators studying systemic sclerosis.

“This is something that Khanna and I aim to move towards creating a proof of concept trial in the near future to test this theory and further advancements in systemic sclerosis treatment and care,” said Dr. Gudjonsson.

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