Focus on Research: A Breakthrough Discovery

Hal Dietz, MD
The Johns Hopkins University
School of Medicine;

Victor A. McKusick Professor of Genetics and Medicine in the Institute of Genetic Medicine;

Director of the Smilow Center for Marfan Syndrome Research;

Howard Hughes Medical Investigator





"I was initially trained as a physician focused on patients with connective tissue disorders, but became frustrated by the lack of progress that I was seeing in patients affected by these conditions. For that reason, I left clinical practice to study genetics, with the sole aim of learning about the mechanisms of connective tissue diseases in order to arrive at new and informed treatment strategies. I still see patients but spend about 80% of my time running a large laboratory with a translational focus - striving to improve the length and quality of life for people with connective tissue disorders like scleroderma and stiff skin syndrome."
- Dr. Hal Dietz

Dr. Hal Dietz and his team at The Johns Hopkins University have made a key discovery that may have broad implications for future scleroderma therapy. In a report published in the November 7, 2013 print issue of the premier scientific journal, Nature, the researchers demonstrated that integrin modulating agents (integrins are molecular receptors that mediate the attachment between a cell and its surroundings) can stop fibrosis in a genetic mouse model of scleroderma-like skin and, more strikingly, that established fibrosis can actually be reversed by the same agents.

Using unique mice bred with the genetic mutation that is the basis of the human disease stiff skin syndrome (SSS), Dr. Hal Dietz and his colleagues at The Johns Hopkins University have greatly increased understanding of the causes of fibrosis, a signature feature of scleroderma. They have recently shown that a culprit is a defect in the way certain cells communicate with their structural scaffolding. Their findings represent a sharp contrast to traditional thinking about scleroderma and may point the way toward developing new drugs for the disease.

While scleroderma rarely runs in families, Dietz’s team was struck by the similarities between scleroderma and the less severe, much rarer condition of SSS, a genetic fibrotic disease, and they suspected that learning more about SSS would shed light on scleroderma.


“There may be a final common pathway by which cells lose their normal control and, even if one condition is genetic and the other is not, they may both funnel down to the same mechanism,” says Dr. Dietz of his combined SSS and scleroderma work. Like other complex, adult-onset autoimmune diseases, animal models of scleroderma replicate some, but not all features of the disease. This gap has slowed work in the scleroderma field.

The Dietz group’s creation of the SSS mouse model marked the first time scientists could breed large numbers of animals to see what is happening in fibrotic tissues at every step along the way—from predisposition to end-stage tissue failure. In the SSS mouse model and, seemingly, in scleroderma, there is a fundamental process that goes awry: cells in the skin lose the ability to attach to the extracellular matrix and to sense their surroundings. Those cells then become activated and stimulate an immune response that causes the surrounding cells to produce excessive amounts of collagen, resulting in fibrotic skin.


What’s most exciting is that the Dietz lab discovered a strategy to suppress the abnormal activation of the immune cells. In doing so, they also found that they could not only prevent, but also reverse established skin fibrosis.


In a previous study (also funded by the Scleroderma Research Foundation and published in Science and Translational Medicine in 2010), they pinpointed the genetic mutation responsible for SSS in a gene for a protein called fibrillin-1, which plays a role in other connective tissue disorders.


In certain types of tissues, including skin, fibrillin-1 helps make up the scaffolding for cells. The specific changes in fibrillin-1 seen in SSS patients were predicted to impair the ability of cells to make contact with fibrillin-1 through bridging molecules called integrins. In the current study, the Dietz team created a line of mice with a genetic variant similar to that found in SSS patients. To test the group’s hypothesis, they also created a line of mice with a variant the team knew would prevent fibrillin-1 from interacting with integrins. As the team expected, both groups of mice developed stiff skin, along with elevated levels of proteins and cells involved in the immune response— much like humans with SSS or scleroderma. “It seemed we were right that the stiff skin syndrome mutation causes the condition by blocking fibrillin’s interaction with integrins,” says Dr. Dietz. “Something else we found was that both types of mice had high levels of integrins in their skin, which made us think their cells were trying to compensate for the lack of fibrillin integrin interaction by making more and more integrin.”

This still left open the question of what was ultimately causing fibrosis, however: was it the integrin levels or the immune response? Dr. Dietz’s team delved deeper into the question by creating mice that had both the SSS mutation and artificially low levels of integrin, and found that the mice never developed abnormal immune response. In fact, the researchers could not distinguish between healthy tissue and diseased tissue in these mice by any laboratory measurement.

The team next tried waiting until mice with the SSS mutation had developed fibrosis, then treating them with specific integrin binding antibodies as well as with TGF-beta neutralizing antibodies. This reversed the mice’s skin fibrosis and immunologic abnormalities. The team also tested the compounds on lab grown human skin cells from scleroderma patients, with the same results. This raises the possibility that scleroderma patients could eventually be treated with similar compounds.

The SRF is optimistic that some of the strategies applied in Dr. Dietz’s laboratory could transition relatively quickly to patients as pharmaceutical companies are already exploring drugs that block some of these molecular targets for other conditions, including cancer.

“A key finding of this study is the unexpected discovery that fibrosis can be reversed. This is a major advance in our thinking about fibrosis. It reveals that the fibrotic process is actually quite dynamic; therefore, when a drug succeeds in preventing excessive production of collagen, existing fibrosis can be diminished,” said David Botstein, Ph.D., the Anthony B. Evnin Professor of Genomics and Director of the Lewis – Sigler Institute for Integrative Genomics at Princeton University, who is also a Scientific Advisor of the Scleroderma Research Foundation.

Beyond its relevance to fibrosis, this project may provide other insights into the disease process in scleroderma. Scleroderma Research Foundation Scientific Advisor Antony Rosen, M.D., who is Vice Dean for Research at The Johns Hopkins University School of Medicine, the Mary Betty Stevens Professor of Medicine and Professor of Cell Biology and Pathology adds that “equally surprising is that the SSS mice have an immune response that targets the identical protein (topoisomerase I) that is targeted in scleroderma. We hope that investigating that similarity—how the immune system gets stimulated and targets that molecule—will tell us a great deal about the underlying mechanism of scleroderma.”

Continuing work in Dietz’s group focuses on better understanding the underlying cellular mechanisms that drive excessive collagen production (fibrosis) in the skin and other tissues of patients with scleroderma and developing inhibitors of these mechanisms that are specific enough that they do not also interfere with other essential cellular processes.

The Scleroderma Research Foundation takes great pride in having brought Dietz’s expertise and talent to scleroderma research. Dr. Luke Evnin, Chairman of the Board of Directors for the SRF says, “Dr. Dietz’s expertise in genetics and connective tissue diseases, together with his phenomenal success in translating his discoveries about the action of fibrillin-1 in Marfan syndrome into therapeutic insights that directly benefit Marfan patients, inspired us to approach him and explore whether there was a productive area of overlap for us.” Dr. Dietz adds, “I credit the Scleroderma Research Foundation with great foresight and wisdom in coming to someone with no track record in scleroderma and saying, “give us your best idea, think broadly, and see if you can help us make progress.”


Scleroderma Research Foundation Media Release

Johns Hopkins University School of Medicine Media Release