Fibulin-5/DANCE has an elastogenic organizer activity that is abrogated by proteolytic cleavage in vivo.
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.
Hirai
Maretoshi
M
Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Ohbayashi
Tetsuya
T
Horiguchi
Masahito
M
Okawa
Katsuya
K
Hagiwara
Akari
A
Chien
Kenneth R
KR
Kita
Toru
T
Nakamura
Tomoyuki
T
D000375:Aging / Q000378:metabolism; D000594:Amino Acid Oxidoreductases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004547:Elastic Tissue / Q000378:metabolism* / Q000648:ultrastructure; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D020894:Microfibrils / Q000378:metabolism* / Q000648:ultrastructure; D012038:Regeneration / Q000502:physiology; D012867:Skin / Q000378:metabolism / Q000648:ultrastructure; D014333:Tropoelastin / Q000378:metabolism*
D016895:Culture Media, Serum-Free; D016326:Extracellular Matrix Proteins; C492373:FBLN5 protein, human; D014333:Tropoelastin; D000594:Amino Acid Oxidoreductases; C445313:LOXL1 protein, human