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Study Could Lead to New Treatments for Tissue Scarring

Potential new druggable therapeutic target for breaking the vicious cycle of tissue scarring in people with scleroderma

A discovery by “Northwestern Scleroderma Program” scientists could lead to potential new treatments for breaking the vicious cycle of tissue scarring in people with scleroderma. Fibrosis or scarring is a hallmark of the disease, and progressive tightening of the skin and lung can lead to serious organ damage and, in some cases death.

The concept centers on findings made by Swati Bhattacharyya, PhD, research assistant professor in Medicine-Rheumatology, and Dr. John Varga, John and Nancy Hughes Distinguished Professor of Rheumatology and director of the Northwestern Scleroderma Program. They identified the role that a specific protein plays in promoting fibrosis, a process similar to the formation of scar tissue. Their results showed how a damage-associated protein called fibronectin (FnEDA) might trigger immune responses that convert normal tissue repair (wound healing) into chronic fibrosis in people with scleroderma. They also found that FnEDA, which is undetectable in healthy adults, was markedly increased in patients with scleroderma.

The study was published April 16 in Science Translational Medicine. This pioneering study, using state of the art experimental approaches, is the first to identify an innate immune pathway for scleroderma fibrosis. The results will shift people’s thinking about the disease, and hopefully open new avenues for its treatment.

Scleroderma is an orphan disease with high mortality and no effective treatment. Bhattacharyya and colleagues previously showed that innate immunity is persistently activated in scleroderma patients. The factors responsible for fibrosis in scleroderma remain largely unknown and although inflammation is implicated, its exact role in fibrosis remained a mystery. To investigate the connection between immunity/inflammation and fibrosis in scleroderma, scientists looked for the factors responsible for persistent innate immune signaling in scleroderma skin biopsies. They discovered that damage-associated protein FnEDA was highly elevated in the scleroderma skin biopsies. Using a genetically engineered mouse that fails to produce FnEDA they found that these mice are resistant to develop skin fibrosis. They then showed that FnEDA triggered an immune response in skin cells that led to fibrosis. Finally they showed that a small molecule inhibitor that specifically blocked the cellular response triggered by FnEDA was able to prevent skin fibrosis in mice. The inhibitor selectively targeted a cellular receptor TLR4, which is linked in inflammation and is known to be elevated in patients with scleroderma. While the current studies focused on scleroderma, the mechanisms uncovered might also underlie more common forms of fibrosis, such as pulmonary fibrosis and liver cirrhosis.

This work has raised the possibility for developing novel therapeutic approaches. Currently, they are developing novel small molecules to selectively block the receptor for FnEDA as a potential anti fibrotic therapy. Future work will attempt to identify a correlation between FnEDA expression and disease complications such as lung fibrosis and pulmonary arterial hypertension.

The multi-disciplinary scleroderma research team included scientists at Northwestern University Feinberg School of Medicine and the University of Michigan. The study was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases grants AR42309 and AR057216.


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