Make It Snappy: Fibulin-5 helps mice stay supple (Connective tissue)
Authors: Davenport R. John 
Published: August 2003

Like overstretched rubber bands, flexible tissues in the body lose their snap with time. Scientists have long wondered what molecular events underlie this degeneration, and researchers have now identified a molecule necessary to maintain the spring: Mice without it develop loose skin, misshapen blood vessels, and flaccid lungs characteristic of older, diseased animals. Having the molecule in hand should help scientists understand how aging and disease distort tissues and might provide a target for reversing the damage.

A protein network that weaves between cells provides an elastic mesh--or matrix--that makes tissues supple and ensures that they bounce back after being stretched. When the network breaks down, tissues deform; floppy lung tissue can lead to emphysema, and distended blood vessels can trigger aneurysms. Although many components of the rubbery matrix are known, the process by which the body establishes and maintains it remains elusive.

Serendipity has led two groups to a key matrix organizer. Scientists had previously fingered a protein--called fibulin-5--that heart cells produce in great abundance and then dump into the space that surrounds them. Wondering whether absence of the protein leads to heart problems, two groups engineered mice lacking the gene that encodes fibulin-5. As expected, the animals exhibited heart deformities, but those problems resulted from unusually droopy tissues rather than from defects specific to the heart: In addition to enlarged blood vessels, the mice also suffered from sagging, loose skin and expanded lungs, signs that the elastic network has broken down. When the groups looked at sections of mouse tissue under a microscope, they found a more loosely woven matrix than that observed in normal mice. Together, the results suggest that fibulin-5 helps organize and maintain the system that gives tissues their bounce.

Fibulin-5's exact role isn't yet clear, but further results suggest that it connects the network to cells by attaching to components from both. Yanagisawa and colleagues found that fibulin-5 binds to cell surface proteins, whereas Nakamura and colleagues discovered that fibulin-5 grasps a protein called elastin, the mesh component that does the stretching. Nakamura and colleagues speculate that fibulin-5 might help preserve tissue pliancy by triggering cells to make new elastin and also by lending structural integrity to the network.

Mice that lack genes for other components of the elastic network die as embryos, whereas the fibulin-5-deficient mice develop normally and have a life-span similar to that of their wild-type siblings. As a result, the new mice offer a much-needed animal model in which to study the system. Such investigations should elucidate how tissues maintain their elasticity and why aging and diseases destroy that resiliency. Fibulin-5 might even provide a target for therapies that aim to reverse breakdown of the network. That idea is still a stretch, but if it pans out, it offers hope for staying supple late in life.

--R. John Davenport

H. Yanagisawa, E. C. Davis, B. C. Starcher, T. Ouchi, M. Yanagisawa, J. A. Richardson, E. N. Olson, Fibulin-5 is an elastin-binding protein essential for elastic fibre development
in vivo.
Nature
415
, 168-171 (2002).
[Abstract]
[Full Text]

T. Nakamura, P. R. Lozano, Y. Ikeda, Y. Iwanaga, A. Hinek, S. Minamisawa, C.-F. Cheng, K. Kobuke, N. Dalton, Y. Takada, K. Tashiro, J. Ross Jr., T. Honjo, K. R. Chien, Fibulin-5/DANCE is essential for elastogenesis
in vivo
.
Nature
415
, 171-175 (2002).
[Abstract]
[Full Text]