L-WNT3A调控Wnt反应细胞自噬水平促进骨质疏松牙槽骨重塑的机制研究

With improvements in esthetics and efficiency, orthodontic treatment becomes acceptable to a growing number of senior patients, and consequently osteoporosis is more often encountered by orthodontists. Since imbalanced alveolar bone remodeling would result in troublesome dental problems, patients suffering osteoporosis are at higher risks of periodontal damage, alveolar bone resorption, and even tooth loss during orthodontic treatment. It is imperative to develop effective strategies to prevent or intervene these osteoporosis-related complications. This project aims to thoroughly study the osteoporotic alveolar bone remodeling process during orthodontic tooth movement, including the potential regulatory effect and mechanisms of Wnt-responsive cells and possible interventions. By establishing orthodontic tooth movement model on osteoporotic Wnt reporter mice and conditional autophagy gene knock-out mice, the osteoporotic alveolar bone remodeling process will be investigated covering tissue turnover, cellular activity, molecular signal interaction, and the potential regulatory role of Wnt-responsive cells autophagy. Furthermore, exogenous Wnt stimulus, liposomal WNT3A, will be tested in its targeted regulatory effects on Wnt-responsive cells autophagic activity and osteoporotic alveolar bone remodeling. Findings from this project would lend evidence to managing orthodontic complications via targeted regulation of Wnt signaling pathway. Development of such biotherapeutics would significantly improve the standard of care in orthodontic clinics.

随着正畸治疗美观性及效率性的不断提高，中老年正畸患者数量增加，由骨质疏松引起的牙槽骨重塑失衡等问题日益凸显。牙周组织破坏、牙槽骨吸收、甚至牙齿松动脱落等正畸并发症极大程度增加了此类患者的治疗风险，探索其有效防治手段是口腔临床亟待解决的问题。本项目从Wnt反应细胞自噬水平出发，深入研究骨质疏松正畸牙移动中牙槽骨重塑过程，并探索其调控机制及干预手段。研究拟采用Wnt信号通路报告小鼠及自噬基因条件敲除小鼠，从组织变化、细胞行为及分子信号交互作用等多个角度分析骨重塑过程中Wnt反应细胞自噬活动规律，考察自噬介导Wnt反应细胞调控骨重塑的作用机制，并在明确外源性L-WNT3A发挥生物学效应的量效规律基础之上，揭示L-WNT3A协同应力刺激靶向调控Wnt反应细胞自噬促进骨质疏松牙槽骨重塑的分子生物机制。研究结果将为口腔临床以Wnt信号通路为靶点生物防治骨质疏松患者正畸并发症提供理论基础和实验依据。

随着正畸治疗美观性及效率性的不断提高，中老年正畸患者数量增加，由骨质疏松引起的牙槽骨重塑失衡等问题日益凸显。牙周组织破坏、牙槽骨吸收、甚至牙齿松动脱落等正畸并发症极大程度增加了此类患者的治疗风险，探索其有效防治手段是口腔临床亟待解决的问题。本研究通过建立骨质疏松小鼠牙移动模型，明确了骨质疏松牙槽骨密度及骨体积分数显著降低，牙移动速率加快，骨重塑过程中Wnt信号应答水平减弱，破骨活动增强，成骨活动降低，牙根吸收明显。且骨质疏松小鼠骨髓间充质干细胞成骨分化、自我更新及克隆形成能力降低，成脂分化能力增强。自噬是介导外源性Wnt信号发挥生物学效应的关键细胞内过程。外源性Wnt信号刺通过调控Wnt反应细胞自噬及凋亡活动，抑制骨质疏松牙槽骨破骨活动，促进成骨活动，从而在一定程度上逆转骨质疏松对牙槽骨重塑过程的不利影响。研究结果将为口腔临床以Wnt信号通路为靶点生物防治骨质疏松患者正畸并发症提供理论基础和实验依据。