Targeted disruption of ephrin B1 in cells of myeloid lineage increases osteoclast differentiation and bone resorption in mice.
Targeted disruption of ephrin B1 in cells of myeloid lineage increases osteoclast differentiation and bone resorption in mice.
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DOI：
10.1371/journal.pone.0032887
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Xing W
中科院分区：
文献类型：
--
作者：
Cheng S;Zhao SL;Nelson B;Kesavan C;Qin X;Wergedal J;Mohan S;Xing W
破坏小鼠I型胶原生成细胞中的肝配蛋白B1会导致严重的颅骨缺损和骨形成减少。由于ephrin B1也在破骨细胞分化过程中表达，并且由于对ephrin B1反向信号在骨吸收中的作用知之甚少，我们检查了ephrin B1条件性敲除小鼠的骨表型，并研究了ephrin B1反向信号对破骨细胞分化和骨吸收活性的作用。髓系细胞中ephrin B1基因的靶向缺失导致TRAP阳性破骨细胞增加和骨吸收引起的骨小梁体积、骨小梁数量和骨小梁厚度减少。组织形态学分析发现，骨形成参数没有改变ephrin B1基因敲除小鼠。用成簇的可溶性EphB 2-Fc处理野生型前体抑制RANKL诱导的多核破骨细胞和骨吸收陷窝的形成。同样的治疗肝配蛋白B1缺乏前体破骨细胞分化和小凹形成的影响不大。类似地，通过EphB 2-Fc处理激活肝配蛋白B1反向信号传导导致来自野生型小鼠但非条件性敲除小鼠的破骨细胞中TRAP、组织蛋白酶K和NFATc 1 mRNA表达的抑制。NHERF 1抗体免疫沉淀显示ephrin B1与NHERF 1在分化的破骨细胞中相互作用。用外源性EphB 2-Fc处理破骨细胞导致ezrin/radixin/moesin的磷酸化减少。我们的结论是髓系产生的肝配蛋白B1是体内骨吸收的负调节因子，肝配蛋白B1的反向信号激活部分通过抑制NFATc 1表达和调节ezrin/radixin/moesin磷酸化状态的机制抑制体外破骨细胞分化。
Disruption of ephrin B1 in collagen I producing cells in mice results in severe skull defects and reduced bone formation. Because ephrin B1 is also expressed during osteoclast differentiation and because little is known on the role of ephrin B1 reverse signaling in bone resorption, we examined the bone phenotypes in ephrin B1 conditional knockout mice, and studied the function of ephrin B1 reverse signaling on osteoclast differentiation and resorptive activity. Targeted deletion of ephrin B1 gene in myeloid lineage cells resulted in reduced trabecular bone volume, trabecular number and trabecular thickness caused by increased TRAP positive osteoclasts and bone resorption. Histomorphometric analyses found bone formation parameters were not changed in ephrin B1 knockout mice. Treatment of wild-type precursors with clustered soluble EphB2-Fc inhibited RANKL induced formation of multinucleated osteoclasts, and bone resorption pits. The same treatment of ephrin B1 deficient precursors had little effect on osteoclast differentiation and pit formation. Similarly, activation of ephrin B1 reverse signaling by EphB2-Fc treatment led to inhibition of TRAP, cathepsin K and NFATc1 mRNA expression in osteoclasts derived from wild-type mice but not conditional knockout mice. Immunoprecipitation with NHERF1 antibody revealed ephrin B1 interacted with NHERF1 in differentiated osteoclasts. Treatment of osteoclasts with exogenous EphB2-Fc resulted in reduced phosphorylation of ezrin/radixin/moesin. We conclude that myeloid lineage produced ephrin B1 is a negative regulator of bone resorption in vivo, and that activation of ephrin B1 reverse signaling inhibits osteoclast differentiation in vitro in part via a mechanism that involves inhibition of NFATc1 expression and modulation of phosphorylation status of ezrin/radixin/moesin.
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