March 7, 2003

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Early Miscues Cause Late Problems in Model of Marfan Syndrome

By studying mice, Johns Hopkins scientists have discovered that excessive activity of an important signaling protein, TGF-beta, likely underlies a variety of problems in Marfan syndrome, including the tendency to develop emphysema, they report in the March issue of Nature Genetics.

The results in mice dramatically improve understanding of TGF-beta's regulation and function and provide a completely new mechanism for changes seen in Marfan syndrome, say the researchers, offering the most feasible
target yet for preventing the life-threatening problems that stem from the connective tissue disorder.

"TGF-beta pulls together what we know clinically about Marfan syndrome with what we know genetically," says study leader Hal Dietz, M.D., who directs the Smilow Center for Marfan Research at Johns Hopkins. "If our findings in mice are supported by clinical evidence of high TGF-beta activity in people with Marfan syndrome, blocking TGF-beta activity may be a reasonable approach to reduce or prevent many features of the syndrome."

In 1991, scientists tied Marfan syndrome to genetic mutations that create a non-functioning fibrillin-1 protein, which normally coats the elastic fibers that help give tissues form and strength. Without fibrillin-1, elastic fibers form, but they are more prone to breaking, explaining some problems seen in Marfan syndrome, including rupture of the aorta, which carries blood away from the heart.

Structural weakness has also been the primary explanation for emphysema, the gradual inflammation and destruction of the tiny air pockets in the lungs. However, the new research shows that not only is TGF-beta activity high, but blocking it during development can prevent lung damage in mice without fibrillin-1, says first author Enid Neptune, M.D., assistant professor in the division of pulmonary and critical care medicine at Johns Hopkins.

"In mice lacking fibrillin-1, excessive TGF-beta activity triggers developmental abnormalities that clearly contribute to the development of emphysema," says Dietz, also a professor of pediatrics and molecular biology and genetics. "Increased TGF-beta activity could contribute to other aspects of Marfan syndrome, as well, because the protein helps regulate cell performance in many tissues, including the bone, heart valves and aorta."

Never before linked to Marfan syndrome, TGF-beta is made inside cells, coupled with other proteins that inactivate it, then shipped out of the cell to dock in nearby connective tissue. When TGF-beta's signal is needed, it is released in a controlled but poorly understood manner, says Dietz.

In two kinds of mice with little or no working fibrillin-1, the scientists discovered that lung tissue held excessive amounts of free, active TGF-beta. Without fibrillin-1 to bind to TGF-beta's inactive complex, the signaling protein is either more available to activation or more likely to get turned on, they found.

"No one's ever really thought of fibrillin-1 or other structural elements as also being potential signal regulators," says Dietz. "We've proven, however, that fibrillin-1 is a critical regulator of TGF-beta availability and activity."

As the fibrillin-1-deficient mice aged, they developed full-fledged emphysema, just like that seen in people, the scientists report. Investigating further, they discovered that extra TGF-beta activity induces death in some lung cells that would normally form additional walls and create smaller air pockets during development. Blocking TGF-beta just before birth prevented lung problems in the offspring, the researchers report.

"This model provides a venue to understanding pathways that may be critical for normal lung development even outside of Marfan syndrome," adds Neptune.

Currently, people diagnosed with Marfan syndrome are followed closely by physicians because of their high risk of life-threatening complications. Treatments to lower blood pressure or otherwise protect the integrity of the aorta are often used, but there is no cure.

Marfan syndrome or a similar disorder affects approximately 200,000 people in the United States, according to the National Marfan Foundation, which sponsored part of the work. As awareness of the disorder has increased,
people are getting diagnosed at younger ages, perhaps offering an opportunity to take advantage of TGF-beta's role as an early change that leads to later problems, notes Dietz.

Authors on the report are Dietz, Neptune, Pamela Frischmeyer, Dan Arking and Loretha Myers of the Johns Hopkins School of Medicine; Tracie Bunton of Dupont Pharmaceuticals Company; Barbara Gayraud and Francesco Ramirez of the Hospital for Special Surgery in New York; and Lynn Sakai of Shriners
Hospital in Portland, Ore.

The Johns Hopkins researchers were funded by the Howard Hughes Medical Institute, the National Institutes of Health, the Michael Murray Fund of the National Marfan Foundation, and the Smilow Foundation.

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