Fibrillin-1 and -2 differentially modulate endogenous TGF-β and BMP bioavailability during bone formation.
Fibrillin-1 and -2 differentially modulate endogenous TGF-β and BMP bioavailability during bone formation.
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DOI：
10.1083/jcb.201003089
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发表时间：
2010-09-20
期刊：
影响因子：
--
通讯作者：
Ramirez F
中科院分区：
文献类型：
--
作者：
Nistala H;Lee-Arteaga S;Smaldone S;Siciliano G;Carta L;Ono RN;Sengle G;Arteaga-Solis E;Levasseur R;Ducy P;Sakai LY;Karsenty G;Ramirez F
细胞外微纤维由骨形成蛋白-1和骨形成蛋白-2组成，通过调节TGF-β和BMP信号传导来调节骨形成。转化生长因子（TGF）-β家族成员对信号传导的细胞外调节正在成为器官形成和组织重塑的关键方面。在这项研究中，我们证明了细胞外微纤维的结构成分-β 1和-2，差异调节TGF-β和骨形态发生蛋白（BMP）在骨中的生物利用度。原纤维蛋白-2-null（Fbn 2 −/−）小鼠表现出低骨量表型，与体内骨形成减少和体外成骨细胞成熟受损相关。这种Fbn 2 −/−表型是由于潜在的TGF-β的不适当激活，选择性地减弱了osterix（成骨细胞成熟的转录调节因子）和I型胶原（骨矿化的结构模板）的表达。从Fbn 1 −/−小鼠培养的成骨细胞也表现出不适当的潜在TGF-β激活，但成熟更快，因为增加了其他基质结合BMP的可用性。额外的体外证据排除了微纤维在支持矿物质沉积中的直接作用。总之，这些发现通过调节内源性TGF-β和BMP信号传导将细胞外微纤维鉴定为骨形成的关键调节剂。
Extracellular microfibrils composed of fibrillin-1 and -2 regulate bone formation through modulation of TGF-β and BMP signaling. 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.
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影响因子：
2.9
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影响因子：
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作者：
Ducy, P;Zhang, R;Karsenty, G
通讯作者：
Karsenty, G