II型糖尿病状态下巨噬细胞调控MSCs成骨分化在种植体周围炎中的作用与机制研究

Type II diabetes mellitus patients with peri-implantitis resulted in significantly more alveolar bone resorption. Previous studies on the topic have largely focused on how to control blood sugar and prevent infection, ignoring the influence of inflammatory microenvironment under type II diabetes mellitus on bone regeneration. Our recent study has found that macrophage polarization is imbalanced in type II diabetes mellitus, which is characterized by excessive polarization of M1.On the other hand, the loss of periodontal ligament around the implant provides physiological conditions for cross-talk between macrophages in the soft tissue and mesenchymal stem cells (MSCs) in the alveolar bone around the implant, and exosomes might be important communication mediators in this cross-talk. Further studies have found that M1 macrophage-derived exosomes are especially rich in microRNAs (miRNAs) that inhibit the osteogenesis of MSCs (such as miR-23 and miR-454). Therefore, we hypothesize that when peri-implantitis combined with Type II diabetes mellitus, the soft tissue around the implant is over-infiltrated with M1-polarized macrophages, and the released exosomes are endocytosed by adjacent alveolar bone MSCs, which ultimately inhibits osteogenic differentiation of MSCs and aggravates peri-implantitis. Based on the above work, this project intends to study the role of macrophage polarization imbalance and exosomes it secret in peri-implantitis under Type II diabetes mellitus, and identify the key miRNA components in the exosomes, expect to discover a potential mechanism for the aggravated peri-implantitis in type II diabetes mellitus.

II型糖尿病状态下，种植体周围炎骨吸收更为严重，既往研究主要集中在控制血糖和预防感染上，忽略了种植体周围炎症微环境改变对成骨细胞的影响。课题组新近发现：II型糖尿病状态下巨噬细胞极化失衡，表现为M1极化过度；另一方面，牙周膜的缺失，为植体周围软组织巨噬细胞和牙槽骨间充质干细胞(MSCs)的“信息交流”提供了条件，而外泌体是两细胞间交流的重要媒介；进一步研究发现M1型巨噬细胞外泌体内富含抑制MSCs成骨分化的miRNAs（如miR-23和miR-454）。因此，我们推测种植体周围炎合并II型糖尿病时，软组织中过度浸润M1极化的巨噬细胞，释放的外泌体被毗邻牙槽骨MSCs内吞，最终抑制成骨再生，加重种植体周围炎。本项目拟在以上工作的基础上，深入研究巨噬细胞极化失衡及其来源外泌体在II型糖尿病种植体周围炎中的作用，明确其中关键的miRNA组分，期望发现II型糖尿病加重种植体周围炎的新机制。

本项目在国家自然科学基金资助下，通过临床对比研究、分子生物学检测以及建立II型糖尿病种植体动物模型，明确了巨噬细胞极化失衡是II型糖尿病种植体周围炎骨吸收严重的细胞学原因；进一步研究发现，种植体周围炎合并II型糖尿病时，软组织中过度浸润的M1极化巨噬细胞，可通过外泌体途径抑制间充质干细胞的成骨分化；另外，在上述导致骨吸收过程中，非编码RNA在巨噬细胞来源外泌体调控间充质干细胞成骨分化中起到关键的作用，最终抑制成骨再生，加重种植体周围炎。上述研究成果，深入探讨了巨噬细胞极化失衡及其来源外泌体在II型糖尿病种植体周围炎中的作用，明确其中关键的调控组分，进一步揭发了II型糖尿病加重种植体周围炎骨吸收更严重的分子机制。