Bidirectional Signaling through EphrinA2-EphA2 Enhances Osteoclastogenesis and Suppresses Osteoblastogenesis
Bidirectional Signaling through EphrinA2-EphA2 Enhances Osteoclastogenesis and Suppresses Osteoblastogenesis
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DOI：
10.1074/jbc.m807598200
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发表时间：
2009-05-22
影响因子：
4.8
通讯作者：
Matsuo, Koichi
中科院分区：
文献类型：
--
作者：
Irie, Naoko;Takada, Yasunari;Matsuo, Koichi
骨骼在一生中不断地被骨吸收破骨细胞和成骨细胞重塑。为了保持骨的体积和质量，破骨细胞和成骨细胞的分化通过这两个细胞系之间和内部的沟通受到严格的调控。在此之前，我们报道了破骨细胞上的ePhinB2配体和成骨细胞上的EphB4受体介导的细胞-细胞相互作用产生双向的反破骨和促进成骨信号进入各自的细胞，推测促进了骨吸收向骨形成的转变。在这里，我们展示了双向的ewitinA2-EphA2信号在起始阶段调节骨重建。在破骨细胞前体细胞中，转录因子c-Fos的受体激活剂能迅速诱导破骨细胞前体细胞表达EPhinA2，但不依赖于c-Fos靶基因产物NFATc1。EphA2受体在破骨细胞前体和成骨细胞中有表达。过表达实验表明，破骨细胞前体中的EphA2和EphA2促进了多核破骨细胞的分化，磷脂酶C-γ2可能介导了ewitinA2的反向信号转导。此外，破骨细胞上的eaffinA2被金属蛋白酶切割，培养上清液中释放的eferinA2促进了破骨细胞的形成。有趣的是，缺乏EphA2的成骨细胞的分化随着碱性磷酸酶、Runx2和Osterix的表达而增强，这表明成骨细胞上的EphA2可能通过上调RhoA活性来产生反成骨细胞信号。因此，EphA2通过促进破骨细胞分化和抑制成骨细胞分化，促进骨重建的起始阶段。
Bone is remodeled constantly throughout life by bone-resorbing osteoclasts and bone-forming osteoblasts. To maintain bone volume and quality, differentiation of osteoclasts and osteoblasts is tightly regulated through communication between and within these two cell lineages. Previously we reported that cell-cell interaction mediated by ephrinB2 ligand on osteoclasts and EphB4 receptor on osteoblasts generates bidirectional anti-osteoclastogenic and pro-osteoblastogenic signals into respective cells and presumably facilitates transition from bone resorption to bone formation. Here we show that bidirectional ephrinA2-EphA2 signaling regulates bone remodeling at the initiation phase. EphrinA2 expression was rapidly induced by receptor activator of NF-kappa B ligand in osteoclast precursors; this was dependent on the transcription factor c-Fos but independent of the c-Fos target gene product NFATc1. Receptor EphA2 was expressed in osteoclast precursors and osteoblasts. Overexpression experiments revealed that both ephrinA2 and EphA2 in osteoclast precursors enhanced differentiation of multinucleated osteoclasts and that phospholipase C gamma 2 may mediate ephrinA2 reverse signaling. Moreover, ephrinA2 on osteoclasts was cleaved by metalloproteinases, and ephrinA2 released in the culture medium enhanced osteoclastogenesis. Interestingly, differentiation of osteoblasts lacking EphA2 was enhanced along with alkaline phosphatase, Runx2, and Osterix expression, indicating that EphA2 on osteoblasts generates anti-osteoblastogenic signals presumably by up-regulating RhoA activity. Therefore, ephrinA2-EphA2 interaction facilitates the initiation phase of bone remodeling by enhancing osteoclast differentiation and suppressing osteoblast differentiation.