Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis
Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis
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DOI：
10.1016/j.cmet.2006.05.012
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发表时间：
2006-08-01
期刊：
影响因子：
29
通讯作者：
Matsuo, Koichi
中科院分区：
文献类型：
--
作者：
Zhao, Chen;Irie, Naoko;Matsuo, Koichi
骨稳态需要在骨吸收破骨细胞和骨形成成骨细胞的活动之间保持微妙的平衡。各种分子协调破骨细胞与成骨细胞的功能，然而，介导破骨细胞-成骨细胞的相互作用，同时在两种细胞类型的信号转导的分子尚未被确定。我们发现破骨细胞表达NFATc 1靶基因Efnb 2（编码ephrinB 2），而成骨细胞表达受体EphB 4，沿着其他ephrin-Eph家族成员。使用增益和功能丧失的实验，我们证明，通过ephrinB 2到破骨细胞前体的反向信号抑制破骨细胞分化，通过抑制破骨细胞c-Fos-NFATc 1级联。此外，通过EphB 4进入成骨细胞的正向信号传导增强了成骨分化，并且成骨细胞中EphB 4的过表达增加了转基因小鼠的骨量。这些数据表明，肝配蛋白-Eph双向信号连接细胞分化的两个主要分子机制-一个在破骨细胞和成骨细胞-从而维持骨稳态。
Bone homeostasis requires a delicate balance between the activities of bone-resorbing osteoclasts and bone-forming osteoblasts. Various molecules coordinate osteoclast function with that of osteoblasts; however, molecules that mediate osteoclast-osteoblast interactions by simultaneous signal transduction in both cell types have not yet been identified. Here we show that osteoclasts express the NFATc1 target gene Efnb2 (encoding ephrinB2), while osteoblasts express the receptor EphB4, along with other ephrin-Eph family members. Using gain- and loss-of-function experiments, we demonstrate that reverse signaling through ephrinB2 into osteoclast precursors suppresses osteoclast differentiation by inhibiting the osteoclastogenic c-Fos-NFATc1 cascade. In addition, forward signaling through EphB4 into osteoblasts enhances osteogenic differentiation, and overexpression of EphB4 in osteoblasts increases bone mass in transgenic mice. These data demonstrate that ephrin-Eph bidirectional signaling links two major molecular mechanisms for cell differentiation - one in osteoclasts and the other in osteoblasts - thereby maintaining bone homeostasis.