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 Sakai, Gerard Karsenty, Francesco Ramirez

Research output: Contribution to journalArticle

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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

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Bone Morphogenetic Proteins
Transforming Growth Factors
Osteogenesis
Biological Availability
Osteoblasts
Microfibrils
Bone and Bones
Physiologic Calcification
Minerals
Collagen
Fibrillin-1
Fibrillin-2
Phenotype

ASJC Scopus subject areas

  • Cell Biology

Cite this

Nistala, H., Lee-Arteaga, S., Smaldone, S., Siciliano, G., Carta, L., Ono, R. N., ... 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

Fibrillin-1 and -2 differentially modulate endogenous TGF-β and BMP bioavailability during bone formation. / Nistala, Harikiran; Lee-Arteaga, Sui; Smaldone, Silvia; Siciliano, Gabriella; Carta, Luca; Ono, Robert N.; Sengle, Gerhard; Arteaga-Solis, Emilio; Levasseur, Regis; Ducy, Patricia; Sakai, Lynn; Karsenty, Gerard; Ramirez, Francesco.

In: Journal of Cell Biology, Vol. 190, No. 6, 20.09.2010, p. 1107-1121.

Research output: Contribution to journalArticle

Nistala, H, Lee-Arteaga, S, Smaldone, S, Siciliano, G, Carta, L, Ono, RN, Sengle, G, Arteaga-Solis, E, Levasseur, R, Ducy, P, Sakai, L, Karsenty, G & Ramirez, F 2010, 'Fibrillin-1 and -2 differentially modulate endogenous TGF-β and BMP bioavailability during bone formation', Journal of Cell Biology, vol. 190, no. 6, pp. 1107-1121. https://doi.org/10.1083/jcb.201003089
Nistala, Harikiran ; Lee-Arteaga, Sui ; Smaldone, Silvia ; Siciliano, Gabriella ; Carta, Luca ; Ono, Robert N. ; Sengle, Gerhard ; Arteaga-Solis, Emilio ; Levasseur, Regis ; Ducy, Patricia ; Sakai, Lynn ; Karsenty, Gerard ; Ramirez, Francesco. / Fibrillin-1 and -2 differentially modulate endogenous TGF-β and BMP bioavailability during bone formation. In: Journal of Cell Biology. 2010 ; Vol. 190, No. 6. pp. 1107-1121.
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