TY - JOUR
T1 - Fibrillin-1 and -2 differentially modulate endogenous TGF-β and BMP bioavailability during bone formation
AU - Nistala, Harikiran
AU - Lee-Arteaga, Sui
AU - Smaldone, Silvia
AU - Siciliano, Gabriella
AU - Carta, Luca
AU - Ono, Robert N.
AU - Sengle, Gerhard
AU - Arteaga-Solis, Emilio
AU - Levasseur, Regis
AU - Ducy, Patricia
AU - Sakai, Lynn Y.
AU - Karsenty, Gerard
AU - Ramirez, Francesco
PY - 2010/9/20
Y1 - 2010/9/20
N2 - 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.
AB - 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.
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U2 - 10.1083/jcb.201003089
DO - 10.1083/jcb.201003089
M3 - Article
C2 - 20855508
AN - SCOPUS:77957204548
SN - 0021-9525
VL - 190
SP - 1107
EP - 1121
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 6
ER -