Spotlight on Research 2007

May 2007 (historical)

Scientists Develop a Mouse Model of Scleroderma

Scientists supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have created a new mouse model for scleroderma, a debilitating disease characterized by thickening of the skin, blood vessels and internal organs. The availability of the new model, the researchers say, will potentially lead to a better understanding of and treatment for the disease in humans. Their research appeared in the January edition of Arthritis & Rheumatism.

Scleroderma is a generalized disease of fibroblasts, says study author Benoit de Crombrugghe, M.D., professor and chairman of the Department of Molecular Genetics at the University of Texas M.D. Anderson Cancer Center. Fibroblasts make connective tissue, which supports the cells that make up the skin, blood vessels and other organs. In scleroderma, the fibroblasts secrete excessive amounts of certain proteins, such as collagen I and III and fibronectin, thus making excessive connective tissue. While there is much scientists don't understand about the process, they have known that a hormone-like substance called transforming growth factor- beta (TGF-) is involved. Skin samples from people with the disease have higher-than-normal levels of this substance, and fibroblasts taken from scleroderma-like skin make higher-than-normal levels of TGF- when put in culture.

There are specific receptors for TGF- on the surfaces of fibroblasts. When TGF- binds to those receptors, it sends signals inside the cell that change the behavior of the cell. Dr. de Crombrugghe and his colleagues sought to create a mouse model of the disease by activating the TGF- receptors on the mouse's fibroblasts. Using genetic techniques, they were able to modify mouse fibroblasts so that the TGF- receptors could be turned on as if they were receiving a constant signal from the growth factor. In other words, the fibroblasts were no longer dependent on TGF- for their activity. Turning on the receptor in fibroblasts of adult mice resulted in symptoms that strongly resembled human scleroderma. "Their skin was thicker, their blood vessel walls were thicker and they lost their hair," says Dr. de Crombrugghe. When the scientists looked at biochemical barometers of the disease--such as collagen I and III and fibronectin--they too were increased, as found in human scleroderma. This mouse model of scleroderma has more severe disease, and reproduces several key features of the human disease.

The model provides direct evidence that TGF- plays a role in fibrosis and scleroderma-like disease. It also provides a new tool to further understanding of the mechanisms of disease and for future testing of potential therapeutics.

Additional support was provided for this research by the Shriners Hospitals for Children.

The mission of the NIAMS, a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at

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Sonnylal S, et al. Postnatal induction of transforming growth factor signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma. ArthritisRheum 2007;56:334-344.