Analysis of Bone Remodeling using Osteopetrotic and Osteosclerotic Mouse Models

1.骨稳态需要骨吸收破骨细胞和成骨细胞活性之间的微妙平衡。不同的分子协调破骨细胞和成骨细胞的功能；然而，在这两种细胞类型中通过同时信号转导来介导破骨细胞-成骨细胞相互作用的分子尚未确定。在这里，我们展示了破骨细胞表达NFATc-1靶基因ePhinB2，而成骨细胞表达受体EphB4，以及其他ePhin-Eph家族成员。通过功能获得和功能丧失实验，我们证明了通过ewitinB2进入破骨细胞前体的反向信号通过抑制破骨细胞生成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，在成骨细胞中过表达EphB4增加了转基因小鼠的骨量。这些数据表明，eaffin-Eph双向信号传递连接了两种主要的细胞分化分子机制--一种在破骨细胞中，另一种在成骨细胞中--从而维持骨内环境的稳定(赵等人，2006年)。转基因(TG)小鼠出现骨硬化，骨基质蛋白表达改变。我们发现在Fral TG成骨细胞中Thbs1和Thbs2的表达减少。Fral TG和非骨硬化性Thbs1-/-Thbs2-/-小鼠共享边缘到边缘咬伤。因此，凝血酶原蛋白表达的减少可能有助于独立于骨硬化症的颅面部畸形(Nishiwaki等人，2006年)。我们还观察到，在Fral TG小鼠中，炎性细胞因子的产生减少，骨折后成骨细胞分化的启动延迟(手稿正在准备中)。

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).