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.
While excess collagen is a hallmark feature of both stiff skin and scleroderma, Dietz and his team have discovered the relation of Fibrilin-1, a connective tissue protein to the skin conditions.
Fibrilin-1 regulates the activity of TGFbeta, a molecule that induces cells to make more collagen. The research found that the stiff skin syndrome and scleroderma mutations prevent fibrilin-1 from interacting with neighbouring cells and lead to increased amounts and activity of TGFbeta, which causes excessive collagen outside cells.
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.