Causes Found for Stiff Skin Conditions PDF Print E-mail
Thursday, 18 March 2010 19:28
By studying the genetics of a rare inherited disorder called stiff skin syndrome, researchers at the Johns Hopkins University School of Medicine have learned more about scleroderma, a condition affecting about one in 5,000 people that leads to hardening of the skin as well as other debilitating and often life-threatening problems. The findings, which appear this week in Science Translational Medicine, open doors to testing new treatments.

"Scleroderma is a common and often devastating condition yet its cause remains mysterious. My greatest hope is that this work will facilitate the development of new and better treatments," says Harry C. Dietz, M.D., the Victor A. McKusick Professor of Genetics and director of the Johns Hopkins William S. Smilow Center for Marfan Syndrome Research.

Also known as systemic sclerosis, scleroderma generally affects previously healthy young adults, causing scarring of skin and internal organs that can lead to heart and lung failure. "Most often individuals with scleroderma do not have other affected family members, precluding use of genetic techniques to map the underlying genes. Instead we turned to a rare but inherited form of isolated skin fibrosis called stiff skin syndrome, hoping to gain a foothold regarding cellular mechanisms that might prove relevant to both conditions," says Dietz.

A number of clues led Dietz and his team to strongly suspect a role for the connective tissue protein fibrillin-1 in these skin conditions. First, excess collagen is a hallmark feature of both stiff skin syndrome and scleroderma. While studying Marfan syndrome, a condition caused by a deficiency of fibrillin-1, the researchers discovered that fibrillin-1 regulates the activity of TGFbeta, a molecule that induces cells to make more collagen. Second, other researchers have shown that duplication of a segment within the fibrillin-1 gene is associated with skin fibrosis in mice. And third, Dietz treated a patient at Johns Hopkins who had both stiff skin syndrome and eye problems associated with Marfan syndrome. "This seemed too much of a coincidence," he says.

So Dietz's team examined patients with stiff skin syndrome and found them to have excessive amounts of fibrillin-1 in the skin. The researchers then sequenced the fibrillin-1 gene in these same patients and found all the stiff skin syndrome mutations clustered in a single region of the fibrillin-1 protein known to interact with neighboring cells. Further examination showed that these mutations prevent fibrillin-1 from interacting with neighboring cells and lead to increased amounts and activity of TGFbeta, which causes excessive collagen outside cells.

The researchers then examined biopsies from patients with scleroderma and found all of the abnormalities seen in stiff skin syndrome. "It appears that fibriillin-1 helps to inform cells about the quality of their surroundings and also provides a mechanism - by concentrating TGFbeta - to induce extra cellular matrix production if the cell senses a deficiency," says Dietz. "A breakdown in signaling coupled with excessive fibrillin-1 and TGFbeta leads to a perfect storm for skin fibrosis in stiff skin syndrome."

While it remains unknown what triggers similar molecular events in scleroderma, these findings do suggest a number of potential treatment strategies, says Dietz.

This study was funded by the Scleroderma Research Foundation, Howard Hughes Medical Institute, Smilow Center for Marfan Syndrome Research, National Marfan Foundation, the National Institutes of Health and Shriners Hospital for Children.

Source: Ascribe
 
More articles :

» Real-World Bosentan Therapy Successful in Pulmonary Arterial Hypertension: Presented at ATS

Real-life experiences in treating patients with pulmonary arterial hypertension with bosentan appears to provide similar efficacy as seen in clinical trials -- despite patients being somewhat older and having more scleroderma, researchers said today...

» Link Between Skin and Stress

To understand the complex relationship between stress/distress and the skin, dermatologist and clinical psychologist Richard G. Fried, MD, PhD, FAAD, of Yardley, Pa., noted it is important to consider the biological response that happens when a...

» New Research Findings May Bring Breakthrough For Scleroderma Patients

Research presented at the European Academy of Dermatology and Venereology in Prague, Czech Republic, suggests that inhibition of the may be a viable therapeutic target in patients.This finding builds on previous research by presenter and lead...

» Immune Therapy Developed for Atherosclerosis

is when plaque builds up in the arteries; and it can cause serious problems in the heart. However new strategies are helping patients combat atherosclerosis; and could change the treatment landscape of heart disease, all together.It was in the...

» New, Non-invasive Test May Help Diagnose Pulmonary Hypertension in Scleroderma

In patients with Systemic Sclerosis (SSc) – or – a condition called pulmonary hypertension (PH) is a leading cause of death. Having PH means the blood pressure between the heart and lungs is elevated.The Need for New Tests for PH in SScThe...

» A System Out of Breath: How Hypoxia Possibly Contributes to the Pathogenesis of Systemic Sclerosis

T. W. van Hal, L. van Bon, and T. R. D. J. RadstakeReceived 20 May 2011; Revised 18 August 2011; Accepted 7 September 2011Systemic sclerosis (SSc) is typified by vascular alterations and immunological disturbances and fibrosis of the skin and...