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Published online March 19, 2007
doi:10.1083/jcb.200611026
The Journal of Cell Biology, Vol. 176, No. 7, 1061-1071
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Hirai et al.
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Article

 Fibulin-5/DANCE has an elastogenic organizer activity that is abrogated by proteolytic cleavage in vivo

Maretoshi Hirai1,2, Tetsuya Ohbayashi1, Masahito Horiguchi1,2, Katsuya Okawa1, Akari Hagiwara1, Kenneth R. Chien3, Toru Kita2, and Tomoyuki Nakamura1

1 Horizontal Medical Research Organization and 2 Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
3 Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02114

Correspondence to Tomoyuki Nakamura: nakatomo{at}kuhp.kyoto-u.ac.jp

Elastic fibers are required for the elasticity and integrity of various organs. We and others previously showed that fibulin-5 (also called developing arteries and neural crest EGF-like [DANCE] or embryonic vascular EGF-like repeat–containing protein [EVEC]) is indispensable for elastogenesis by studying fibulin-5–deficient mice, which recapitulate human aging phenotypes caused by disorganized elastic fibers (Nakamura, T., P.R. Lozano, Y. Ikeda, Y. Iwanaga, A. Hinek, S. Minamisawa, C.F. Cheng, K. Kobuke, N. Dalton, Y. Takada, et al. 2002. Nature. 415:171–175; Yanagisawa, H., E.C. Davis, B.C. Starcher, T. Ouchi, M. Yanagisawa, J.A. Richardson, and E.N. Olson. 2002. Nature. 415:168–171). However, the molecular mechanism by which fiblin-5 contributes to elastogenesis remains unknown. We report that fibulin-5 protein potently induces elastic fiber assembly and maturation by organizing tropoelastin and cross-linking enzymes onto microfibrils. Deposition of fibulin-5 on microfibrils promotes coacervation and alignment of tropoelastins on microfibrils, and also facilitates cross-linking of tropoelastin by tethering lysyl oxidase-like 1, 2, and 4 enzymes. Notably, recombinant fibulin-5 protein induced elastogenesis even in serum-free conditions, although elastogenesis in cell culture has been believed to be serum-dependent. Moreover, the amount of full-length fibulin-5 diminishes with age, while truncated fibulin-5, which cannot promote elastogenesis, increases. These data suggest that fibulin-5 could be a novel therapeutic target for elastic fiber regeneration.

Abbreviations used in this paper: BAPN, ß-aminopropionitrile; DANCE, developing arteries and neural crest EGF-like; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HSF, human skin fibroblast; LOX, lysyl oxidase; LOXL, LOX-like.


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