3BP2-deficient mice are osteoporotic with impaired osteoblast and osteoclast functions
3BP2-deficient mice are osteoporotic with impaired osteoblast and osteoclast functions
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DOI：
10.1172/jci45843
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发表时间：
2011-08-01
影响因子：
15.9
通讯作者：
Rottapel, Robert
中科院分区：
文献类型：
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作者：
Levaot, Noam;Simoncic, Paul D.;Rottapel, Robert
破骨细胞的骨吸收和成骨细胞的骨形成之间的良好平衡维持骨稳态。在巨像症患者中，由SH 3结构域结合蛋白2（SH 3BP 2）编码的3BP 2的功能获得性突变引起囊性病变，并激活破骨细胞，导致颅面异常。然而，关于野生型3BP 2在调节骨稳态中的功能知之甚少。在这里，我们已经表明，3BP 2是所需的成骨细胞和破骨细胞的正常功能。初步分析显示，尽管骨吸收受损，但由于骨形成减少，Sh 3bp 2（-/-）小鼠发生骨质疏松症。我们证明了使用相互骨髓嵌合体，在体内成骨细胞和破骨细胞室的细胞内在缺陷。此外，Sh 3bp 2（-/-）成骨细胞在体外不能成熟并形成矿化结节，而Sh 3bp 2（-/-）破骨细胞在体外扩散较差，不能有效降解牙本质基质。最后，我们表明，3BP 2是所需的Abl激活成骨细胞和Src激活破骨细胞，并证明了在体外缺陷的每种细胞类型的恢复分别表达这些激酶的活化形式。这些发现揭示了3BP 2衔接蛋白在成骨细胞功能和协调破骨细胞和成骨细胞谱系中的骨稳态信号中的意想不到的作用。
A fine balance between bone resorption by osteoclasts and bone formation by osteoblasts maintains bone homeostasis. In patients with cherubism, gain-of-function mutations in 3BP2, which is encoded by SH3-domain binding protein 2 (SH3BP2), cause cystic lesions with activated osteoclasts that lead to craniofacial abnormalities. However, little is known about the function of wild-type 3BP2 in regulating bone homeostasis. Here we have shown that 3BP2 is required for the normal function of both osteoblasts and osteoclasts. Initial analysis showed that Sh3bp2(-/-) mice developed osteoporosis as a result of reduced bone formation despite the fact that bone resorption was impaired. We demonstrated using reciprocal bone marrow chimeras, a cell-intrinsic defect of the osteoblast and osteoclast compartments in vivo. Further, Sh3bp2(-/-) osteoblasts failed to mature and form mineralized nodules in vitro, while Sh3bp2(-/-) osteoclasts spread poorly and were unable to effectively degrade dentine matrix in vitro. Finally, we showed that 3BP2 was required for Abl activation in osteoblasts and Src activation in osteoclasts, and demonstrated that the in vitro defect of each cell type was restored by the respective expression of activated forms of these kinases. These findings reveal an unanticipated role for the 3BP2 adapter protein in osteoblast function and in coordinating bone homeostatic signals in both osteoclast and osteoblast lineages.