Molecular pathway ID’d as key driver of scarring in scleroderma
Study: Inhibitor treatments could help mitigate fibrosis in multiple disorders
The molecular signaling pathway EGFR-STAT1 is key for driving fibrosis (scarring) in scleroderma, according to a new study.
The findings suggest that treatments designed to inhibit this pathway could be used to help mitigate fibrosis in scleroderma and other disorders that are characterized by excessive scarring. The study, “EGFR-STAT1 pathway drives fibrosis initiation in fibroinflammatory skin diseases,” was published in Nature Communications.
Inhibiting EGFR-STAT1 pathway could help control fibrosis in scleroderma
Scleroderma is characterized by inflammation and scarring, which can affect the skin and various other organs throughout the body. Inflammation and scarring are closely linked, but they don’t always occur simultaneously. Some disorders, such as scleroderma, are marked by both inflammation and fibrosis, while others are characterized by inflammation but not fibrosis.
In this study, scientists sought to better understand why fibrosis is a feature of some inflammatory skin diseases but not others. The scientists conducted in-depth analyses of cellular activity using samples from people with several different diseases, including disorders that cause scarring, such as scleroderma and lupus, as well as non-fibrotic diseases like atopic dermatitis and psoriasis.
“Treatments for fibrosis are an enormously unmet need,” Richard Flavell, PhD, co-senior author of the study at Yale University School of Medicine, said in a university news story. “Better understanding these conditions will likely yield new medicines to help patients.”
The researchers found that a signaling protein called STAT1 was substantially more active in patients with fibrotic diseases. Further tests showed that EGFR (epidermal growth factor receptor), a signaling protein that’s previously been implicated in driving fibrosis, is able to activate STAT1, leading to changes in cellular activity that ultimately promote the formation of scar tissue.
Our findings elucidate a mechanism by which EGFR directly [activates] STAT1 to drive fibrosis gene expression [activity] profile in fibroblasts of fibroinflammatory skin conditions.
Notably, STAT1 can also be activated by another protein, known as JAK. Medicines that inhibit JAK are effective in some diseases characterized by inflammation alone, but have generally been less effective in diseases marked by both inflammation and fibrosis. The researchers found that EGFR activates STAT1 in a manner independent from JAK, which they said may help explain why JAK inhibitors have generally not shown good efficacy in fibrotic diseases.
“Our findings elucidate a mechanism by which EGFR directly [activates] STAT1 to drive fibrosis gene expression [activity] profile in fibroblasts of fibroinflammatory skin conditions,” the researchers wrote. Fibroblasts are structural cells that play key roles in making scar tissue.
The findings suggest that inhibiting the EGFR-STAT1 pathway could be key for controlling fibrosis in scleroderma, the researchers said. They noted that it may be possible to inactivate this pathway without substantially inhibiting processes necessary for the body to maintain health, which should help minimize side effects.
Epiregulin may be therapeutic target in many fibrotic diseases
In previous work, the same team had found that levels of epiregulin, a protein that’s known to activate EGFR, are elevated in people with scleroderma. In a separate study, the team developed a novel antibody targeting the epiregulin protein. The study, “Sclerotic GVHD and Scleroderma Share Dysregulated Gene Expression that is Ameliorated by EREG Therapeutic Antibody,” was published in Blood.
“[Antibody-mediated] neutralization of [epiregulin] could be a potential therapeutic approach for treatment of [scleroderma] skin and lung fibrosis,” the scientists wrote.
In the study, the researchers demonstrated that their anti-epiregulin antibody reduced fibrosis signatures in skin samples from people with graft-versus-host disease, a condition that can arise as a complication of bone marrow or stem cell transplants and cause fibrosis in a manner that the researchers said shares many molecular mechanisms with scleroderma.
“What really stood out was that the epiregulin signal, like we had seen before in scleroderma, was really highlighted in patients with this fibrotic graft-versus-host disease,” said Ian Odell, MD, PhD, study co-senior author at Yale. The researchers noted that the similarity across these diseases indicates that targeting epiregulin may be a widely applicable therapeutic strategy in many fibrotic diseases.
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