Yang Qiudong, Xiao Junhong, Liu Yuqi, Yang Zhengkun, Wang Chuan, Sun Jiahui, Wang Huiyi, Liu Heyu, Wang Xiaoxuan, Ma Li, Huang Xin, Cao Zhengguo
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China; Department of Periodontology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
Cell Signal. 2025 Mar;127:111572. doi: 10.1016/j.cellsig.2024.111572. Epub 2024 Dec 19.
Periodontitis (PD) is twice as prevalent in diabetics compared to nondiabetics, and diabetes-associated PD is characterized by increased inflammation and aggravated tissue damage. Pyroptosis has recently been implicated in diabetes-associated PD; however, the underlying mechanisms remain largely unknown, resulting in a lack of effective treatments. In this study, we investigated the role of methyltransferase-like 3 (METTL3) in macrophage pyroptosis and found that it inhibits the osteogenic differentiation of osteoblasts via pyroptotic macrophages in a diabetes-associated periodontitis mouse model. Further analysis and validation revealed that nod-like receptor family pyrin domain-containing 3 (NLRP3) is a target of METTL3, with its mRNA stability regulated through a binding of insulin-like growth factor 2 binding protein 3 (IGF2BP3)-dependent pathway. Additionally, local injection of adeno-associated virus 9 (AAV9) demonstrated that METTL3 deficiency in macrophages significantly ameliorates periodontal inflammation and alveolar bone loss in diabetes-associated PD mice. Collectively, our findings indicate that METTL3-mediated modulation of NLRP3 expression is a crucial factor in macrophage pyroptosis during diabetes-associated PD progression. This suggests that the METTL3/IGF2BP3/NLRP3 axis is a novel and promising target for the improvement of periodental inflammation and alveolar bone loss in diabetes-associated PD.
与非糖尿病患者相比，牙周炎（PD）在糖尿病患者中的患病率是其两倍，且糖尿病相关的PD具有炎症增加和组织损伤加重的特征。最近发现细胞焦亡与糖尿病相关的PD有关；然而，其潜在机制仍 largely 未知，导致缺乏有效的治疗方法。在本研究中，我们调查了甲基转移酶样 3（METTL3）在巨噬细胞焦亡中的作用，发现在糖尿病相关牙周炎小鼠模型中，它通过焦亡巨噬细胞抑制成骨细胞的成骨分化。进一步的分析和验证表明，含核苷酸结合寡聚化结构域样受体家族 pyrin 结构域 3（NLRP3）是 METTL3 的一个靶点，其 mRNA 稳定性通过胰岛素样生长因子 2 结合蛋白 3（IGF2BP3）依赖性途径的结合来调节。此外，局部注射腺相关病毒 9（AAV9）表明，巨噬细胞中 METTL3 缺陷显著改善了糖尿病相关 PD 小鼠的牙周炎症和牙槽骨丢失。总的来说，我们的研究结果表明，METTL3 介导的 NLRP3 表达调节是糖尿病相关 PD 进展过程中巨噬细胞焦亡的关键因素。这表明 METTL3/IGF2BP3/NLRP3 轴是改善糖尿病相关 PD 中牙周炎症和牙槽骨丢失的一个新的且有前景的靶点。
