Tissue Scarring in Scleroderma Linked To Key Protein

A study entitled “Fibronectin^EDA Promotes Chronic Cutaneous Fibrosis Through Toll-Like Receptor Signaling” recently published in Science Translational Medicine reports the discovery of the role of a new protein, fibronectin extra domain A, in scleroderma. The discovery may explain what causes the onset of the disease in patients.

Scleroderma, also known as systemic sclerosis, is an autoimmune disease characterized by skin thickening, a process known as fibrosis. While in some types, this hardening is confined to skin in head, face, and feet. In more severe cases of the disease, it affects internal organs such as kidneys, heart, lungs and intestine. The disease currently lacks viable FDA-approved treatments and is associated with high mortality rates among its patient population.

In this study, Swati Bhattacharyya, PhD, research assistant professor in Medicine-Rheumat and colleagues identified fibronectin extra domain A (FnEDA) as a key player in promoting fibrosis. They observed first in skin biopsies of scleroderma patients that FnEDA was significantly increased, and when performed functional studies with mice lacking this protein it prevents the development of fibrosis. In cells, the authors found FnEDA induced fibrosis by triggering an immune response. Accordingly, the team had previously reported a persistent innate immune response being active in scleroderma patients. Using a small molecule that inhibited the cells’ immune response the authors prevented skin fibrosis in mice.

Bhattacharyya commented, “Our results show how a damage-associated protein called fibronectin (FnEDA) might trigger immune responses that convert normal tissue repair into chronic fibrosis in people with scleroderma,” Bhattacharyya said. “We also found that FnEDA, which is undetectable in healthy adults, was markedly increased in the skin biopsies of patients with scleroderma.”

John Varga, MD, John and Nancy Hughes Distinguished Professor of Rheumatology and director of the Northwestern Scleroderma Program and study last author noted, “This pioneering study using state of the art experimental approaches is the first to identify an innate immune pathway for scleroderma fibrosis. We expect that the results will shift our thinking about the disease, and hopefully open new avenues for its treatment.”