Two separate research groups funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have discovered that the molecule EGR-1 (early growth response 1), which regulates gene expression, plays a central role in the development of fibrosis, a condition in which organ-supporting tissue becomes thick, hard, and rigid, hindering normal tissue and organ function. Controlling EGR-1, say the scientists, could be a potential therapy for such disorders as scleroderma and pulmonary fibrosis. Their findings have been reported in the American Journal of Pathology.
Fibrosis is a disorder of the extracellular matrix, the mesh of proteins like collagen that makes up the body's connective tissue. It is a factor in scleroderma, among other diseases, and can affect many of the body's organs, including the lungs, liver, and skin. Its consequences can be devastating, even leading to death. Recent research has shown that cells in fibrotic tissue receive the wrong molecular signals, causing too many extracellular proteins to be made. One possible way to approach the fibrosis problem, scientists say, might be to try to interrupt such signals at critical points in the cellular pathways that they travel.
The two research groups, headed by Carol Feghali-Bostwick, Ph.D., at the University of Pittsburgh School of Medicine and John Varga, M.D., at Northwestern University's Feinberg School of Medicine, took separate approaches in discovering the importance of EGR-1. The University of Pittsburgh group induced fibrosis in mouse and human fibroblasts (cells that make up the extracellular matrix) by utilizing a signaling protein called IGFBP-5 (insulin-like growth factor binding protein 5). The Northwestern team administered the antibiotic bleomycin to induce scleroderma in mice. Both research teams found that the experimentally produced fibrosis was associated with abnormally elevated EGR-1 activity. Furthermore, when they produced fibrosis in cells or in mice lacking EGR-1, the amounts of fibrosis were dramatically reduced. In further support of the findings, the Pittsburgh group found that EGR-1 levels were higher in lung tissues and fibroblasts of people with pulmonary fibrosis compared to controls. EGR-1, concluded the scientists, appears to be essential for the development of fibrosis, making it a potential target for therapy. The two studies also showed that independent signaling pathways, such as those for IGFBP-5 and bleomycin, both converge on EGR-1 to create fibrosis.
Fibrosis is a common disorder and a serious complication of many diseases. It is still considered hard to treat, with no currently approved therapies. Because the understanding of fibrosis is a major unmet medical need, any fresh insights into the disease process might open the door for novel therapies.
In addition to receiving NIAMS funding, the University of Pittsburgh work had support from the National Heart Lung and Blood Institute, the American Lung Association, the American Heart Association Pennsylvania/Delaware affiliate, and the Uehara Memorial Foundation. Support for the Northwestern University work also came from the U.S. Department of Defense.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health (NIH), 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 http://www.niams.nih.gov.
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Yasuoka H, Hsu E, Ruiz X, Steinman R, Choi A, Feghali-Bostwick C. The fibrotic phenotype induced by IGFBP-5 is regulated by MAPK activation and Egr-1-dependent and �independent mechanisms. American Journal of Pathology 2009;175(2):605-615.
Wu M, Melichian D, de la Garza M, Gruner K, Bhattacharyya S, Barr L, Nair A, Shahrara S, Sporn P, Mustoe T, Tourtellotte W, Varga J. Essential roles for early growth response transcription factor Egr-1 in tissue fibrosis and wound healing. American Journal of Pathology 2009;175(3):1041-1055.