Molecular Mechanisms of Regulation of Bone Remodeling and Orthodontic Tooth Movement by Vascular Endothelial Growth Factor

摘要 延长正畸治疗时间可能会影响与口腔健康相关的生活质量，以及 它还与各种副作用密切相关，如外部牙根吸收、龋齿病变和 打开牙周膜。正畸治疗的持续时间在很大程度上取决于拔牙率。 运动，这主要是由骨重建决定的。骨改建是终生持续的 用新骨替换旧的骨组织。目前临床上加速牙齿的方法 运动包括侵入性的外科手术，以刺激骨骼重塑。迫切需要 开发临床适用的非手术方法来促进骨改建和加速牙齿 有动静。研究人员的长期目标是开发临床适用的药理作用。 通过促进牙槽骨显著加速正畸牙移动的药剂 改建。骨重建的水平受到激素、细胞因子、前列腺素、 和机械加载。初步研究数据表明，细胞因子血管内皮细胞 生长因子-A显著增加人卵巢癌细胞的增殖、迁移和侵袭潜能 成骨细胞。血管内皮生长因子-A还增加成骨细胞产生的RANKL/OPG比率，促进 破骨细胞形成。早期的研究表明，局部注射血管内皮细胞生长因子在小鼠体内显著 增加正畸牙齿移动率，而中和抗血管内皮生长因子抗体有 相反的效果。然而，其分子机制尚不清楚。总的目标是 本建议旨在确定血管内皮生长因子-A促进骨重建和骨修复的分子机制。 加速牙齿移动。具体目标是：1)鉴定血管内皮生长因子-A受体(VEGFR-1和/或 血管内皮生长因子受体-2)和细胞内信号通路(S)导致成骨细胞增殖增加， 成骨细胞迁移和侵袭以及RANKL/OPG比值增加和诱导 体外破骨细胞形成；2)：检测局部注射特定激动剂和拮抗剂的效果 VEGFR-1和/或VEGFR-2在口腔牙槽骨上靠近上颌第一磨牙的表达 活体改建和正畸牙齿移动。首先，我们将使用特定的激动剂和拮抗剂 VEGFR-1或VEGFR-2及其诱导的细胞内信号通路研究细胞内 血管内皮生长因子-A诱导的信号通路在成骨细胞中的作用。第二，我们将研究 VEGFR-1或VEGFR-2特异性激动剂和拮抗剂对正畸牙率的影响 局部注射这些因子对小鼠的运动和骨重建的影响。 健康影响：目前的应用探索了一种机制，为发展 治疗药物可显著减少数百万正畸患者的治疗时间和副作用 并将丰富我们对控制骨重建的分子机制的理解， 这将使我们能够为相关的临床应用设计新的疗法和治疗剂。

Abstract Prolonged orthodontic treatment duration may compromise oral-health related quality of life, and is also closely associated with various side effects such as external root resorption, carious lesions and open gingival embrasures. Orthodontic treatment duration is largely decided by the rate of tooth movement, which is chiefly determined by bone remodeling. Bone remodeling is the life-long continuous replacement of the old bone tissue with new bone. Current clinical methods to accelerate tooth movement involve invasive surgical procedures to stimulate bone remodeling. There is a critical need to develop clinically applicable non-surgical methods to enhance bone remodeling and accelerate tooth movement. The long-term goal of the researcher is to develop clinically applicable pharmacological agents to significantly accelerate orthodontic tooth movement through enhancing alveolar bone remodeling. The level of bone remodeling is closely regulated by hormones, cytokines, prostaglandins, and mechanical loading. Preliminary study data demonstrated that the cytokine vascular endothelial growth factor (VEGF)-A significantly increased proliferation, migration and invasion potentials of osteoblastic cells. VEGF-A also increased RANKL/OPG ratio produced by osteoblastic cells, promoting osteoclast formation. Earlier studies demonstrated that local injection of VEGF in mice significantly increased the rate of orthodontic tooth movement, while neutralizing anti-VEGF antibody had the opposite effects. However, the molecular mechanisms are yet to be elucidated. The overall objective of this proposal is to identify the molecular mechanisms used by VEGF-A to enhance bone remodeling and accelerate tooth movement. The specific aims are: 1): Identify the VEGF-A receptor (VEGFR-1 and/or VEGFR-2) and intracellular signaling pathway(s) leading to the increased osteoblast proliferation, migration and invasion, as well as the increased RANKL/OPG ratio by osteoblasts and induction of osteoclast formation in vitro; 2): Examine the effects of local injection of specific agonists and antagonists of VEGFR-1 and/or VEGFR-2 at the buccal alveolar region close to the maxillary first molar on bone remodeling and orthodontic tooth movement in vivo. First, we will use specific agonists and antagonists of VEGFR-1 or VEGFR-2 and the intracellular signaling pathways they induce to study the intracellular signaling pathways induced by VEGF-A leading to effects in osteoblasts. Second, we will study the effects of the specific agonists and antagonists of VEGFR-1 or VEGFR-2 on the rate of orthodontic tooth movement and bone remodeling with local injections of these factors in mice. Health impact: The current application explores a mechanism that paves road for development of therapeutic agents to significantly reduce treatment time and side effects for millions of orthodontic patients, and will enrich our understanding of the molecular mechanisms controlling bone remodeling, which will allow us to design new therapies and therapeutic agents for related clinical applications.