Analysis of Bone Remodeling using Osteopetrotic and Osteosclerotic Mouse Models

使用骨质疏松和骨硬化小鼠模型分析骨重塑

基本信息

批准号：
17390420
负责人：
MATSUO Koichi
金额：
$ 9.98万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390420/
关键词：
Osteoimmunology Bone remodeling ephrin c-Fos Osteoclast cytokine OPG Auditory ossicles

项目摘要

1. 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 NFATc 1 target gene 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-NFATc 1 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 (Zhao et al., 2006).2. Fral transgenic (Tg) mice develop osteosclerosis and exhibit altered expression of bone matrix proteins. We found that expression of Thbsl and Thbs2 was reduced in Fral Tg osteoblasts. Fral Tg and non-osteosclerotic Thbsl-/-Thbs2-/-mice share an edge-to-edge bite. Therefore, reduced expression of thrombospondins may contribute to craniofacial dysmorphism independently of osteosclerosis (Nishiwaki et al., 2006). We also observed that inflammatory cytokine production is reduced in Fral Tg mice and initiation of osteoblastic differentiation is delayed after bone fracture (manuscript in preparation).

1. 骨稳态需要骨吸收破骨细胞和骨形成成骨细胞的活动之间存在微妙的平衡。各种分子协调破骨细胞与成骨细胞的功能；然而，尚未鉴定出通过两种细胞类型同时信号转导介导破骨细胞-成骨细胞相互作用的分子。在这里，我们发现破骨细胞表达 NFATc 1 靶基因 ephrinB2，而成骨细胞表达受体 EphB4 以及其他 ephrin-Eph 家族成员。通过功能获得和功能丧失实验，我们证明通过 ephrinB2 向破骨细胞前体发出反向信号，通过抑制破骨细胞生成的 c-Fos-NFATc 1 级联来抑制破骨细胞分化。此外，通过EphB4进入成骨细胞的正向信号增强了成骨分化，并且成骨细胞中EphB4的过度表达增加了转基因小鼠的骨量。这些数据表明，肝配蛋白-Eph 双向信号传导连接细胞分化的两种主要分子机制（一种在破骨细胞中，另一种在成骨细胞中），从而维持骨稳态（Zhao 等，2006）。2． Fral 转基因 (Tg) 小鼠出现骨硬化并表现出骨基质蛋白表达改变。我们发现Fral Tg成骨细胞中Thbs1和Thbs2的表达降低。 Fral Tg 和非骨硬化 Thbs1-/-Thbs2-/- 小鼠共享边对边咬合。因此，血小板反应蛋白表达的减少可能会导致颅面畸形，而与骨硬化无关（Nishiwaki et al., 2006）。我们还观察到，Fral Tg 小鼠中炎症细胞因子的产生减少，骨折后成骨细胞分化的开始延迟（手稿正在准备中）。