Under Embargo Till: 17:00 UTC February 17, 2009
Posted: 17:00 UTC 02/17/2009

Tumor Suppressor Could Someday Regulate Fibrotic Diseases

Tuesday, February 17, 2009

A new study finds a cellular signaling pathway that could be responsible for some connective tissue diseases such as scleroderma. The study also suggests a new function for tumor suppressors in combating fibrotic diseases. The study is published in the February issue of Developmental Cell. The study was co-authored by Dr. Philippe Soriano, Professor of Developmental and Regenerative Biology and Oncological Sciences at Mount Sinai School of Medicine, and Dr. Lorin E. Olson, Postdoctoral fellow at Mount Sinai, and was initiated at the Fred Hutchinson Cancer Research Center in Seattle, Washington.

Systemic sclerosis, or scleroderma, is a group of autoimmune diseases that affects an estimated 300,000 people in the United States. These diseases are characterized by chronic autoimmune reactions, microvascular restriction, and widespread fibrosis of the skin and other organs or excessive levels of connective tissue. This can take place in the gastrointestinal system, skeletal muscle, heart, kidney, and lungs, and frequently can result in organ failure and death. “There is no known cause or cure for the diseases collectively known as scleroderma. This research could result in the development of treatments to alleviate the often painful symptoms associated with these kinds of diseases,” said Dr. Soriano.

For the study, gene targeted mice were manipulated with mutations that increase signaling activity by the Platelet Derived Growth Factor Receptor-alpha (PDGFRa). Increased PDGFRa activation in embryos leads to connective tissue hyperplasia and disrupts organ function, and increased PDGFRa activation in adult mice lead to systemic fibrotic disease in multiple organs. Loss of the tumor suppressor gene (Ink4a/Arf) accelerated fibrosis when combined with PDGFRa activation, revealing a possible new role for tumor suppressors in regulating fibrotic diseases.

This work provides insight into the signaling pathways involved in connective tissue disease and highlights a new role for tumor-suppressor genes in the regulation of fibrotic conditions. “This research is also important because it establishes an animal model for testing novel therapies for blocking aberrant PDGFRa signaling in human disease,” said Dr. Soriano.

Source: Mount Sinai Medical Center

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Time Stamp: 2/17/2009 at 17:00:00 UTC