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Protein's Crucial Role In Developing Elastic Fibers

Sagging skin and stiff, twisted arteries are considered a natural, if unfortunate, aspect of growing old that is caused by loss of elastic fiber in the body.

In addition, this loss can lead to some forms of chronic lung disease, such as emphysema.

Now, new findings by researchers at the University of California, San Diego (UCSD) School of Medicine offer insight into the role of a recently discovered protein in the development of elastic fibers, and the potential for future therapies to combat these and other aspects of aging.

In a paper published in today's issue of the journal Nature, investigators in the UCSD Institute of Molecular Medicine (IMM) describe the crucial role of a protein called fibulin-5, or DANCE (Developing Arteries and Neural Crest EGF-like), in the generation and organization of elastic fibers in mice.

"The elastic fiber system is essential in the structure and function of various types of organs which require elasticity, such as large arteries, lungs, and skin," said Tomoyuki Nakamura, M.D., Ph.D., UCSD project scientist and the paper's first author. "Currently, it is not known how elastic fibers develop; thus, there is no way to regenerate elastic fiber which tends to degrade in aging and in some diseases."

Working in the lab of senior author Kenneth Chien, M.D., Ph.D., professor of medicine and IMM director, Nakamura first discovered fibulin-5 two years ago. To understand its function, Nakamura and his team generated mice without fibulin-5 and noticed striking differences as compared to normal rodents.

Although the mice without fibulin-5 survived to adulthood, their skin hung in loose, wrinkled masses, and their stretched cheeks were puffed out.

When the researchers looked at the animal's internal organs, they saw a stiff, twisted aorta and evidence of severe emphysema, including ruptured air sacs and bubble-like spaces throughout the lungs. In some of the mice, they noted pelvic hernias and enlarged gallbladders and spleens.

By electron microscopy, the researchers found that the mice exhibited a severely disorganized elastic fiber system, which is composed of elastin protein and microfibril proteins, and is responsible for elasticity in the whole body.

The scientists noted that fibulin-5 might provide anchorage of elastic fibers to cells, thereby acting to stabilize and organize elastic fibers in the skin, lungs and blood vessels.

Aside from elastin itself, no other single protein has been shown to be essential for the development of elastic fibers and their maturation in multiple mammal organ systems, the researchers said.

In their Nature paper, they showed that severe emphysema in the mice without fibulin-5 is caused by disorganization of elastic fibers in the lung, similar to human emphysema, where elastic fibers are degraded. Smoking has been identified as a cause of human emphysema, which affects 1.8 million Americans.

Smoking triggers release of enzymes that degrade elastic fibers in the lungs, resulting in the destruction of air sacs and an inability to expand and contract the lungs in a normal manner. Individuals with emphysema have difficulty transferring oxygen from their lungs to the bloodstream.

"We believe that defects in the fibulin-5/DANCE pathway could play an important role in emphysema. The next step will require the precise identification of the Fibulin5/DANCE receptor," noted Chien.

"Currently, there is no way to regenerate lost elastic fibers," Nakamura said. "If a way is found to maintain or regenerate these fibers, fibulin-5 may be an indispensable ingredient for the recipe. We also believe that elastic fiber regeneration could be of either cosmetic or medical value, to restore elasticity to aging or injured skin."

In addition to Nakamura and Chien, authors of the paper were Pilar Ruiz Lozano, Ph.D., assistant project scientist, Yasuhiro Ikeda, M.D., Ph.D., postdoctoral fellow, Susumu Minamisawa, M.D., Ph.D., postdoctoral fellow, Ching-Feng Cheng, M.D., postdoctoral fellow, Nancy Dalton, staff research associate, and John Ross, Jr., M.D., professor of medicine, UCSD Institute of Molecular Medicine and UCSD-Salk Program in Molecular Medicine; Yoshitaka Iwanaga, M.D., Ph.D., postdoctoral fellow, UCSD Institute of Molecular Medicine and The Scripps Research Institute; Aleksander Hinek, M.D., professor, The Hospital for Sick Children, Toronto, Ontario; Kazuhiro Kobuke, M.D., Ph.D., post doctoral fellow and Tasuku Honjo, M.D., Ph.D., professor, Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Yoshikazu Takada, M.D., Ph.D., assistant professor, The Scripps Research Institute; and Kei Tashiro, M.D., Ph.D., associate professor, Center for Molecular Biology and Genetics, Kyoto University, Kyoto, Japan.

Funding was provided by the National Institutes of Health, the Jean LeDucq Foundation and the American Heart Association. - By Sue Pondrom

[Contact: Sue Pondrom]






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