DLX3调控牙槽骨骨改建机制的研究

The alveolar bone is the basis of periodontal supporting tissue. The alveolar ridge loss and absorption strongly affects the following implantation and prosthodontic treatment. It is a clinical challenge and research hotspot to sustain the alveolar bone mass. Interestingly, the patients affected with Tricho-dento-osseous (TDO) syndrome can remain sufficient bone mass in a long time, the mechanism of this phenomenon is of high study value. So we propose the hypothesis that suppressing DLX3 locally in the alveolar bone can selectively reduce the bone loss by inhibiting the osteoclastic process associated with IFN-γ. Our study plans to imitate the ‘favorable phenotype’ of the TDO patients by mouse model. The functional assay will be made to investigate the preservation of alveolar bone volume after suppressing Dlx3 expression with virus vector in normal murine alveolar socket. The differentially expressed genes (DEG) will be detected by RNA sequencing, and the DEG would be compared with those from the bone marrow stem cells of the TDO patient. In this way we propose to find out the key downstream factors in the remodeling of the alveolar ridge in the extraction site. Phenotype replication and reversal experiments will be carried out by activating and inhibiting IFN-γ in the tooth extraction fossa, and then the osteoclast activity will be detected respectively to verify the role of IFN-γ in the process of osteoclastic bone resorption. Our study will provide the theoretical basis for the artificial regulation of the alveolar ridge remodeling, and offer a breakthrough for the management of the patients affected with alveolar bone loss.

牙槽骨是牙周支持组织的基础，各种原因导致的牙槽骨骨缺损及其萎缩吸收，影响后续修复治疗，如何保持牙槽骨骨量一直是临床难点和研究热点。DLX3基因突变的毛-牙-骨综合征患者在拔牙后仍能长期保持较丰满的骨量，其机制值得深入研究，因此本研究提出“在牙槽骨局部抑制DLX3基因，可经IFN-γ等细胞因子抑制破骨细胞，减少牙槽骨吸收”的科学假设。本研究拟用小鼠模拟患者的“有利表型”，在正常小鼠牙槽骨中抑制Dlx3基因表达后拔牙，观察剩余牙槽骨的骨量和骨质；通过RNA测序检测差异表达基因，初步筛选下游基因；通过在拔牙窝激活及抑制IFN-γ进行表型复制及逆转实验，分别检测破骨活动以验证IFN-γ在牙槽骨破骨过程中的作用。本研究将为人为调控、减少牙槽骨吸收提供理论基础，临床转化后可为牙槽骨缺损患者的后续治疗带来新进展。

如何减少牙槽骨的萎缩吸收一直是口腔临床的难点和研究热点。DLX3基因突变的毛-牙-骨综合征患者颅骨及颌骨骨板增厚、骨密度增高，且牙槽骨在拔牙后吸收较少，能够长期保持较为丰满的骨量，其机制值得深入研究。在本研究中，对小鼠拔牙后，在拔牙窝分别置入浸润了生理盐水和可抑制Dlx3基因表达的腺病毒的明胶海绵，以此构建小鼠牙槽骨缺损及愈合模型，取样后组织学检查发现Dlx3基因表达抑制后牙槽窝成骨更早、骨量更多，提示本研究成功“复制”了毛-牙-骨综合征患者的“有利表型”；对Dlx3基因抑制小鼠和对照小鼠的牙槽窝组织进行高通量测序，检测到了一系列差异表达基因，在其中筛选了20余个与牙颌面发育、成骨破骨高度相关的基因，待进一步验证。本研究将为人为调控、减少牙槽骨吸收提供理论基础，临床转化后可为牙槽骨缺损患者的后续治疗带来新进展。