Protein Identified as Key Player in Skin Fibrosis

A skin sample from a four-month old mouse with skin fibrosis (right) showed higher level of elastin fibre (stained blue to black) than in the skin from a normal mouse (left). Credit: Colin Jamora

A skin sample from a four-month old mouse with skin fibrosis (right) showed higher level of elastin fibre (stained blue to black) than in the skin from a normal mouse (left). Credit: Colin Jamora

A discovery by scientists in India and the U.S. uncovers some of the mystery behind the mechanism of scleroderma, a little-understood but prevalent skin condition.

Collagen and elastin fibres give healthy skin its flexibility and suppleness. A build-up of these fibres however turns skin tough and scaly, as is seen in a condition called skin fibrosis or scleroderma.

In a new collaborative study, teams led by Dr. Colin Jamora from the IFOM-inSTEM Joint Research Laboratory in Bangalore and Dr. Shyni Varghese from the University of California employed an unusual strategy and identified a key player in this condition — a protein called Fibulin-5. This holds  promise for possible treatment options for a disease that has no known cure. Their findings were published in the Nature Communications journal earlier this month.

Scleroderma is not merely a cosmetic inconvenience. “The fibrosis could spread and can involve internal organs like the oesophagus, stomach, bowels, lungs, kidneys, heart and even blood vessels, muscles and joints,” said Dr. Jamora in an email interview. Hard and fibrous tissues affect how these organs work and can be fatal.

Most research on fibrotic diseases has focused on collagen, which accounts for around 75% of the fibrotic tissue. This group however, chose to investigate elastin, which composes a smaller portion (8%) of the fibrotic tissue.

Getting the right model

Previous studies had shown an abundance of a protein called Snail in cases of kidney fibrosis, lung fibrosis, and liver fibrosis. By engineering mice whose skin produced high levels of Snail, the researchers found it was possible to induce skin fibrosis. They now had their model organism.

These mice showed all symptoms of skin fibrosis including abundant elastin fibre. Since it was known that elastin production depends on another protein called Fibulin-5, Jamora and team decided to focus on Fibulin-5’s role in the disease. As expected, the transgenic mice showed spiked levels of Fibulin-5, as did the skin tissues of human patients with skin fibrosis..

Moreover, when Fibulin-5 was blocked in these mice, elastin content of their skin reduced and skin thickening as well as inflammation could be prevented. “The connection between  Fibulin-5 and inflammation was unexpected,” says Dr. Jamora. “What Fibulin-5 does is increase the stiffness of the skin and in doing so, causes the cells within the tissue to respond by enhancing the inflammatory response.”

No Fibulin, no problem

The discovery of a single protein that apparently plays such a vital role in the development of a disease opens doors for possible treatment options, for example inhibiting Fibulin-5 in fibrotic tissue to arrest the spread of the condition. This is what the teams are working on next, according to their press release.

An estimated three lakh Americans have scleroderma, but though there has been no nationwide epidemiological study on the incidence of scleroderma in India, Dr. Jamora suspects the figures might be higher here. “When I began this work at the University of California, San Diego, it was somewhat difficult to obtain samples from patients to confirm whether our findings in mice are relevant to the human disease.  However, when I moved to India, obtaining scleroderma samples were quite easy.”