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Getting Under the Skin of Scleroderma

New model of the disease may spur drug development

Summary

HHMI researchers have developed a mouse model of scleroderma. Their studies have uncovered some of the molecular pathways that go awry to cause the disease.

 

Highlights

  • Scientists and clinicians have long puzzled over systemic sclerosis, the most common—and severe—form of the skin disease scleroderma.
  • HHMI researchers have developed a mouse model of scleroderma, and their studies are pointing the way to potential new drug therapies for the disease. 

Scientists and clinicians have long puzzled over systemic sclerosis, the most common—and severe—form of the skin disease scleroderma. With no warning, a healthy 30- or 40-year-old person begins developing thick patches of skin on their body, and then more serious symptoms: trouble breathing or swallowing, digestive issues, and joint pain. Their skin and internal organs also gradually harden and there’s no effective treatment. Those with the most severe forms of the disease can die from complications if their lung tissue hardens.

Now, Howard Hughes Medical Institute (HHMI) researchers have developed a mouse model of scleroderma. Their studies of the affected animals have uncovered some of the molecular pathways that go awry to cause the hardening, or fibrosis, associated with the disease. By targeting those pathways with drugs, the disease can not only be prevented, but even reversed. Their studies were published in the October 10, 2013, issue of Nature.

“Systemic sclerosis has really been considered a very mysterious disorder,” says HHMI investigator Harry C. Dietz of the Johns Hopkins University, the senior author of the new paper. “There’s been a lot of descriptive work on what happens to patients, but very little information uncovered about what causes it.”

Dietz’s team didn’t set out to focus on systemic sclerosis; instead, they had set their sights on a different form of scleroderma called stiff skin syndrome. Stiff skin syndrome is much rarer, is genetically passed from parents to children, and affects people at birth rather than later in life. The disease is also less severe—typically only causing fibrosis of the skin, rather than internal organs. A few years ago, Dietz and his colleagues had identified a gene mutation carried by those with the disease. So they began genetically engineering mice with the same gene mutation, expecting the animals to develop skin fibrosis. 

“By the time the mice were three months old, they had dense skin fibrosis, which is what we expected,” says Dietz. “But then they also began developing signs of other forms of scleroderma including the immunologic abnormalities typical of systemic sclerosis,” he says.

The gene mutation carried by the mice caused a change to a protein called fibrillin-1, which resides in the material between cells called the extracellular matrix. The extracellular matrix provides structural support to the tissues and also binds to and communicates with cells through bridging molecules called integrins. Notably, the mutations causing stiff skin syndrome that were replicated in the mice impair integrin binding to fibrillin-1, preventing cells from properly interacting with their surroundings. In the affected animals, failure of proper communication between the matrix and a type of immature immune cell leads to increased production of integrins in an attempt to compensate. Dietz’s team also observed immune cell activation and release of chemical factors that recruit additional immune cells and promote fibrosis.  

“We don’t know exactly how good this model is in recapitulating the steps of systemic scleroderma in humans yet,” says Dietz. “But it’s certainly the most powerful model that we’ve ever had.”

To see if they could stop the observed cascade of events, Dietz’s group turned to an antibody that promotes the interaction between integrins and their matrix-binding partners. When they gave mice with the fibrillin mutation the antibody, it not only prevented skin fibrosis, but also all of the immune system changes that they’d observed as well. Next, the scientists tested other manipulations aimed at modulating the cellular response to altered cell-matrix interactions; they were shocked to find that these treatments not only prevented autoimmunity and fibrosis, but could reverse established disease in older mice.

“This is one of the first, and the most dramatic, illustrations that fibrosis can be reversed,” says Dietz. “I was quite surprised and quite thrilled.”

The drugs used in the mice aren’t immediately useful in people, but the new knowledge on which cellular pathways and proteins are involved in scleroderma point researchers toward some existing drugs that could be tested in people with systemic sclerosis.

Since people with systemic sclerosis—unlike those with stiff skin syndrome—don’t actually have mutations in fibrillin-1, Dietz and his colleagues are now studying how incorporation of fibrillin-1 into the extracellular matrix becomes dysregulated in the disease. They also want to know whether aspects of the same pathway are responsible for other forms of tissue fibrosis, such as those seen in advanced diabetes, Crohn’s disease, and heart fibrosis.