Fibrillin-1 and -2 differentially modulate endogenous TGF-β and BMP bioavailability during bone formation

Harikiran Nistala, Sui Lee-Arteaga, Silvia Smaldone, Gabriella Siciliano, Luca Carta, Robert N. Ono, Gerhard Sengle, Emilio Arteaga-Solis, Regis Levasseur, Patricia Ducy, Lynn Y. Sakai, Gerard Karsenty, Francesco Ramirez

Research output: Contribution to journalArticle

101 Scopus citations

Abstract

Extracellular regulation of signaling by transforming growth factor (TGF)-β family members is emerging as a key aspect of organ formation and tissue remodeling. In this study, we demonstrate that fibrillin-1 and -2, the structural components of extracellular micro-fibrils, differentially regulate TGF-β and bone morphogenetic protein (BMP) bioavailability in bone. Fibrillin-2-null (Fbn2-/-) mice display a low bone mass phenotype that is associated with reduced bone formation in vivo and impaired osteoblast maturation in vitro. This Fbn2-/- phenotype is accounted for by improper activation of latent TGF-β that selectively blunts expression of osterix, the transcriptional regulator of osteoblast maturation, and collagen I, the structural template for bone mineralization. Cultured osteoblasts from Fbn1-/- mice exhibit improper latent TGF-β activation as well, but mature faster because of increased availability of otherwise matrix-bound BMPs. Additional in vitro evidence excludes a direct role of micro-fibrils in supporting mineral deposition. Together, these findings identify the extracellular microfibrils as critical regulators of bone formation through the modulation of endogenous TGF-β and BMP signaling.

Original languageEnglish (US)
Pages (from-to)1107-1121
Number of pages15
JournalJournal of Cell Biology
Volume190
Issue number6
DOIs
StatePublished - Sep 20 2010

ASJC Scopus subject areas

  • Cell Biology

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    Nistala, H., Lee-Arteaga, S., Smaldone, S., Siciliano, G., Carta, L., Ono, R. N., Sengle, G., Arteaga-Solis, E., Levasseur, R., Ducy, P., Sakai, L. Y., Karsenty, G., & Ramirez, F. (2010). Fibrillin-1 and -2 differentially modulate endogenous TGF-β and BMP bioavailability during bone formation. Journal of Cell Biology, 190(6), 1107-1121. https://doi.org/10.1083/jcb.201003089