Molecular Analyses of Osteoblastic Niche and its Application with the Development of Nano Science

为了了解参与调控和病理的骨形成因子的机制，我们一直在研究与微环境有关的分子基础。我们发现，CIZ通过改变成骨细胞的信号转导参与了骨信息的调节。CIZ和ECM蛋白调节细胞的附着和转录。BMP是骨骼信息中最关键的细胞因子，并参与生态位调节。骨细胞的生态位和细胞在这一位置的调节还没有很好地阐明。由于局部和全身激素的相互作用对骨形成的协调调节很重要，所以我们重点研究甲状旁腺激素(PTH)。这种系统荷尔蒙控制通过调节局部靶组织发挥作用，而局部靶组织又在反馈环路中调节上游信号。甲状旁腺激素受体转基因小鼠在TH…细胞中特异性表达活性形式的甲状旁腺激素受体更多的成骨细胞系具有高骨量表型。在这些小鼠中，OPN缺乏进一步增加了骨量。骨形成也被发现由抑制BMP的ANA和Cnot7控制。表观连接和甲状旁腺激素依赖的调节由M-CSF和MCP也被发现是重要的。骨的再生需要适当的药物和适当的给药系统相结合来控制细胞的行为。然而，由于载体的可获得性，多种药物用于治疗骨骼的输送变得复杂。本研究的目的是探索一种选择性EP4受体激动剂(EP4A)与低剂量骨形态发生蛋白2(BMP-2)联合给药的新系统。EP4A和低剂量BMP-2纳米凝胶的联合治疗有效地激活了骨细胞，通过形成内外皮质板和骨髓组织来再生颅骨，从而再生出与完整颅骨相似的结构。EP4A增强低剂量BMP-2诱导的细胞分化和成骨细胞转录事件的激活。这些数据表明，EP4A和低剂量BMP-2通过纳米凝胶的联合输送为骨修复提供了一种新的系统。较少

To understand the mechanism of boneformation factors that are involved in the regulation and pathology, we have been examining molecular bases with respect to the micro environment. We identified that and CIZ is involved in the regulations ob bone information by altering the signaling of osteoblasts. CIZ and ECM proteins are regulating cell attachment and transcription. BMP is a most critical cytokine for bone information and implicated in niche regulation. Niche for bone cells and the regulation of cells in such location has not been well elucidated. As interaction of local and systemic hormone is important for coordinate regulation of bone formation we focused on parathyroid hormone (PTH). Such systemic hormonal control exerts its effect through the regulation of local target tissues, which in turn regulate upstream signals in a feedback loop. Parathyroid hormone receptor (PPR) transgenic mice expressing a constitutively active form of the receptor (caPPR) specifically in cells of th … More e osteoblast lineage have a high bone mass phenotype. In these mice, OPN deficiency further increased bone mass. Bone formation was also found to be controlled by ANA and Cnot7 that inhibit BMP. Epigentic link and PTH dependent regulation by M-CSF and MCP is also found to be important. Regeneration of bone requires the combination of appropriate drugs and an appropriate delivery system to control cell behavior. However, the delivery of multiple drugs to heal bone is complicated by the availability of carriers. The aim of this study was to explore a new system for delivery of a selective EP4 receptor agonist (EP4A) in combination with low-dose bone morphogenetic protein 2 (BMP-2). Combination treatment with EP4A and low-dose BMP-2 in nanogel efficiently activated bone cells to regenerate calvarial bone by forming both outer and inner cortical plates as well as bone marrow tissue to regenerate a structure similar to that of intact calvaria. EP4A enhanced low-dose BMP-2-induced cell differentiation and activation of transcription events in osteoblasts. These data indicate that combined delivery of EP4A and low-dose BMP-2 via nanogel-based hydrogel provides a new system for bone repair. Less