FOXO1对破骨细胞生成和功能的影响及其机制的研究

发布时间：2018-12-28 13:50

【摘要】：牙列缺损和牙列缺失是口腔医学中的常见疾病。随着经济和社会的发展，种植体修复已经成为其重要的治疗措施之一，长期的临床试验也表明种植体修复是一项十分成功的治疗方案。然而种植体植入后仍然面临着一定的风险，比如种植体失败脱落及周围炎症等，其中又以种植体周围炎为常见和多发的症状。种植体周围炎是指种植体周围软组织炎症，并常伴随着周围牙槽骨的吸收和丧失。破骨细胞是体内唯一具有骨吸收功能的一种多核巨细胞，它来源于单核/巨噬细胞系，通过单核前体细胞融合成多核巨细胞并最终成熟，在骨吸收过程中发挥着主要的作用。因此，了解破骨细胞的生成及其作用机制对于预防种植体周围炎导致的骨吸收的发生具有重要的意义。研究发现叉头框（Forhead box，，FOX）蛋白家族O的三种亚族（FOXO1，FOXO3，FOXO4）在破骨细胞中均有表达，其中以FOXO1的表达量最高。破骨细胞与树突状细胞和巨噬细胞拥有共同的前体细胞系，最近的研究显示FOXO1能够介导树突状细胞和巨噬细胞在炎症反应中对相关靶基因的调控。鉴于FOXO1与单核细胞系的上述关系，我们猜测FOXO1与破骨细胞的生成和作用可能具有一定的相关性，而这种相关性是否通过FOXO1直接作用产生，其作用机制是什么目前尚无直接而系统的报道。本实验利用Cre-LoxP转基因动物模型将FOXO1于髓系单核/巨噬细胞系统中特异性敲除，从而研究FOXO1在破骨生成及其功能中的作用。体内研究发现，FOXO1敲除对于小鼠颅骨表面经RANKL刺激后的骨吸收代谢具有抑制作用。体外研究也证明FOXO1的敲除对破骨细胞的生成和吸收活性具有抑制作用。此外，FOXO1在破骨细胞生成过程中的表达量和核转移率均明显提高，并与RANKL的刺激具有时间依存性。本研究还从分子生物学角度初步揭示FOXO1在破骨生成中受MAPK信号通路调控，同时，FOXO1通过调节相关转录因子、受体及蛋白的表达影响破骨细胞的生成及其功能。本研究证实了FOXO1在破骨生成中受RANKL及其下信号游通路调控，同时FOXO1通过调节破骨相关分子及蛋白的表达来调控破骨细胞生成及其功能。证明了FOXO1在破骨代谢中的作用，为种植体周围炎牙槽骨吸收的预防和治疗带来了新的思路。
[Abstract]:Dentition defect and dentition defect are common diseases in stomatology. With the development of economy and society, implant restoration has become one of the most important treatment measures. The long-term clinical trials also show that implant restoration is a very successful treatment. However, implants still face some risks, such as implant failure and peripheral inflammation, in which peri-implant inflammation is a common and frequent symptom. Periimplant inflammation refers to the inflammation of the surrounding soft tissue, which is often accompanied by the absorption and loss of the alveolar bone around the implant. Osteoclasts are the only multinucleated giant cells with bone resorption in vivo. They are derived from mononuclear / macrophage cell lines and fused into multinucleated giant cells through mononuclear precursor cells, which play a major role in the process of bone resorption. Therefore, understanding the formation and mechanism of osteoclasts is of great significance in preventing bone resorption caused by periimplant inflammation. It was found that three subfamilies (FOXO1,FOXO3,FOXO4) of Forhead box,FOX protein family O were expressed in osteoclasts, and FOXO1 was the most expressed in osteoclasts. Osteoclasts share a common precursor cell line with dendritic cells and macrophages. Recent studies have shown that FOXO1 mediates the regulation of dendritic cells and macrophages by related target genes in inflammatory responses. In view of the above relationship between FOXO1 and monocyte cell lines, we speculate that there may be some correlation between FOXO1 and osteoclast formation and action, and whether this correlation is directly induced by FOXO1. There is no direct and systematic report on the mechanism of its action. In order to study the role of FOXO1 in osteoclast formation and its function, the specific knockout of FOXO1 in medullary mononuclear / macrophage system was studied by using Cre-LoxP transgenic animal model. It was found in vivo that FOXO1 knockout could inhibit bone resorption and metabolism on the surface of mouse skull stimulated by RANKL. In vitro studies also showed that FOXO1 knockout inhibited the formation and absorption of osteoclasts. In addition, the expression of FOXO1 in osteoclast formation and the rate of nuclear metastasis were significantly increased, and were time-dependent with the stimulation of RANKL. This study also revealed that FOXO1 is regulated by MAPK signaling pathway in osteoclast formation from a molecular biological point of view. At the same time, FOXO1 affects the formation and function of osteoclasts by regulating the expression of transcription factors, receptors and proteins. This study demonstrated that FOXO1 is regulated by RANKL and its underlying signaling pathway in osteoclast formation, and that FOXO1 regulates osteoclast formation and its function by regulating the expression of osteoclast-associated molecules and proteins. It is proved that FOXO1 plays an important role in osteoclast metabolism and provides a new idea for the prevention and treatment of alveolar bone resorption in periimplant.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R783.6

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