期刊
JOURNAL OF CELL BIOLOGY
卷 190, 期 6, 页码 1107-1121出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201003089
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资金
- National Institutes of Health [AR42044, AR49698]
- Shriners Hospitals for Children
- National Marfan Foundation
Extracellular regulation of signaling by transforming growth factor (TGF)-beta 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-beta 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-beta 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-beta 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-beta and BMP signaling.
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