The role of mechanotransductively-induced HIF1α stabilization for the regulation of orthodontic tooth movement

机械传导诱导的 HIF1α 稳定在正畸牙齿移动调节中的作用

• 批准号: 318600394
• 负责人: Privatdozent Dr. Christian Kirschneck
• 金额: --
• 依托单位: Poliklinik für Kieferorthopädie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/318600394?language=en
• 关键词: role; mechanotransductively; induced; HIF1; stabilization

For orthodontic tooth movement, a sterile-inflammatory, immunological process at the cellular-molecular level, a mechanical force is transmitted to a tooth. This creates pressure and tension zones in the periodontal ligament (PDL), where bone resorption and bone building processes take place, which enable tooth movement in the direction of force. In our own preparatory work within the framework of the DFG project KI2105/1-1, we examined in the rat (in vivo) and in human PDL fibroblasts (in vitro), whether the hypoxia-associated transcription factor HIF-1α is stabilized during orthodontic force application and tooth movement in the PDL and whether this stabilization continues to increase under the influence of nicotine, which may explain the previously observed potentiation of periodontal bone loss. In addition, the project investigated whether HIF-1α is rather regulated by hypoxia or rather non-hypoxically (e.g. by mechanotransduction / inflammation). Our results indicate a significant increase in HIF1α stabilization in the PDL during force application (tooth movement) compared to controls. Surprisingly, nicotine did not have an additive effect on this HIF1α induction either with or without force application, so that the previously observed potentiation in the PDL cannot be explained by an increased expression of HIF1α or hypoxic states. Further in vitro results indicate that the regulation of HIF1α in the PDL in the context of tooth movement is predominantly controlled by the force application itself (mechanotransduction), whereas hypoxic effects seem to play only a minor role. In addition to human PDL fibroblasts, macrophages also play an important role as immune cells, on the one hand through secretion of cytokines and chemokines, on the other hand as direct progenitor cells of osteoclasts. In the context of the proposed project, the actual role and significance of HIF1α for orthodontic tooth movement and its regulation at the molecular-cellular level is to be clarified. To this end, the extent, localization, effects and a possible mechanism of a mechanotransductively induced stabilization or inhibition (siRNA silencing) of the transcription factor HIF1α in human PDL fibroblasts and macrophages or in the (peri)dental tissue is to be investigated in established in vitro and in vivo models of orthodontic tooth movement. Because HIF1α regulates more than 100 genes by transcriptional activation, which are in part already described in relation to orthodontic tooth movement (cell proliferation and migration, angiogenesis, inflammation, osteoclastogenesis), and since HIF1α also seems to have an inhibitory effect on force-induced bone formation, it can be assumed that HIF1α plays a key role in the regulation of orthodontic tooth movement.

对于正畸牙齿移动，在细胞分子水平上的无菌炎症免疫过程，机械力被传递到牙齿。这在牙周膜（PDL）中产生了压力和张力区，在那里发生骨吸收和骨构建过程，这使得牙齿能够在力的方向上移动。在DFG项目KI 2105/1-1的框架内我们自己的准备工作中，我们在大鼠（体内）和人PDL成纤维细胞中进行了检查（体外），缺氧相关转录因子HIF-1α是否在正畸力施加和PDL中的牙齿移动期间稳定，以及这种稳定性是否在尼古丁的影响下继续增加，这可以解释先前观察到的牙周骨损失的增强。此外，该项目还研究了HIF-1α是受缺氧还是非缺氧调节（例如，通过机械转导/炎症）。我们的研究结果表明，与对照组相比，在施力（牙齿移动）过程中，牙周膜中HIF 1 α的稳定性显著增加。令人惊讶的是，尼古丁对这种HIF 1 α诱导没有累加效应，无论是否施加力，因此先前观察到的PDL增强不能通过HIF 1 α表达增加或缺氧状态来解释。进一步的体外研究结果表明，在牙齿移动的背景下，牙周膜中HIF 1 α的调节主要由力的施加本身（机械转导）控制，而缺氧效应似乎只起次要作用。除人PDL成纤维细胞外，巨噬细胞也作为免疫细胞发挥重要作用，一方面通过分泌细胞因子和趋化因子，另一方面作为破骨细胞的直接祖细胞。在拟议项目的背景下，HIF 1 α对正畸牙齿移动及其在分子细胞水平上的调控的实际作用和意义有待澄清。为此，将在已建立的正畸牙齿移动的体外和体内模型中研究人PDL成纤维细胞和巨噬细胞或（牙周）牙齿组织中转录因子HIF 1 α的机械转导诱导稳定或抑制（siRNA沉默）的程度、定位、效应和可能机制。由于HIF 1 α通过转录激活调节100多个基因，这些基因在正畸牙齿移动（细胞增殖和迁移，血管生成，炎症，破骨细胞生成）中已经部分描述，并且由于HIF 1 α似乎也对力诱导的骨形成具有抑制作用，因此可以假设HIF 1 α在正畸牙齿移动的调节中起关键作用。