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

B12 SENGLENistala, H., Lee-Arteaga, S., Smaldone, S., Siciliano, G., Carta, L., Ono, R., Sengle, G., Arteaga- Solis, E., Levasseur, R., Ducy, P., Sakai, L., Karsenty, and G., Ramirez, F., J Cell Biol. 2010 Sep 20;190(6):1107-21. doi: 10.1083/jcb.201003089.

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 microfibrils, 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 microfibrils 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.

 

Pubmed

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