二甲双胍通过调节成骨细胞和破骨细胞分化减少根尖周炎的骨吸收。

Metformin Reduces Bone Resorption in Apical Periodontitis Through Regulation of Osteoblast and Osteoclast Differentiation.

机构信息

Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan; Department of Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan; College of Bio-Resources and Agriculture, National Taiwan University, Taipei, Taiwan.

Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan; Department of Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan.

出版信息

J Endod. 2023 Sep;49(9):1129-1137. doi: 10.1016/j.joen.2023.07.005. Epub 2023 Jul 16.

DOI:10.1016/j.joen.2023.07.005

PMID:37454872

Abstract

INTRODUCTION

We have previously demonstrated that auxiliary metformin therapy promotes healing of apical periodontitis. Here we aimed to investigate the effects of metformin on osteoblast differentiation and osteoclast formation in cultured cells and rat apical periodontitis.

METHODS

Murine pre-osteoblasts MC3T3-E1 and macrophages RAW264.7 were cultured under hypoxia (2% oxygen) or normoxia (21% oxygen) and stimulated with receptor activator of nuclear factor-κB ligand (RANKL) when indicated. Metformin was added to the cultures to evaluate its anti-hypoxic effects. Expressions of osteoblast differentiation regulator runt-related transcription factor 2 (RUNX2), RANKL, and osteoclast marker tartrate-resistant acid phosphatase (TRAP) were assessed by Western blot. Apical periodontitis was induced in mandibular first molars of 10 Sprague-Dawley rats. Root canal therapy with or without metformin supplement was performed. Periapical bone resorption was measured by micro-computed tomography. Immunohistochemistry was used to examine RUNX2, RANKL, and TRAP expressions.

RESULTS

Hypoxia suppressed RUNX2 expression and enhanced RANKL synthesis in pre-osteoblasts. TRAP production increased in macrophages after hypoxia and/or RANKL stimulation. Metformin reversed hypoxia-induced RUNX2 suppression and RANKL synthesis in pre-osteoblasts. Metformin also inhibited hypoxia and RANKL-enhanced TRAP synthesis in macrophages. Intracanal metformin diminished bone loss in rat apical periodontitis. Comparing with vehicle control, cells lining bone surfaces in metformin-treated lesions had significantly stronger expression of RUNX2 and decreased synthesis of RANKL and TRAP.

CONCLUSIONS

Alleviation of bone resorption by intracanal metformin was associated with enhanced osteoblast differentiation and diminished osteoclast formation in rat apical periodontitis. Our results endorsed the role of metformin as an effective medicament for inflammatory bone diseases.

摘要

简介

我们之前已经证明辅助二甲双胍治疗可促进根尖周炎的愈合。在这里，我们旨在研究二甲双胍在体外培养的细胞和大鼠根尖周炎中对成骨细胞分化和破骨细胞形成的影响。

方法

将鼠前成骨细胞 MC3T3-E1 和巨噬细胞 RAW264.7 在低氧（2%氧气）或常氧（21%氧气）下培养，并在有需要时用核因子-κB 受体激活剂配体（RANKL）刺激。将二甲双胍添加到培养物中以评估其抗缺氧作用。通过 Western blot 评估成骨细胞分化调节剂 runt 相关转录因子 2（RUNX2）、RANKL 和破骨细胞标志物抗酒石酸酸性磷酸酶（TRAP）的表达。在 10 只 Sprague-Dawley 大鼠的下颌第一磨牙中诱导根尖周炎。进行根管治疗，同时或不补充二甲双胍。通过微计算机断层扫描测量根尖周骨吸收。免疫组织化学用于检测 RUNX2、RANKL 和 TRAP 的表达。

结果

低氧抑制前成骨细胞中的 RUNX2 表达并增强 RANKL 的合成。低氧和/或 RANKL 刺激后，巨噬细胞中 TRAP 的产生增加。二甲双胍逆转了前成骨细胞中低氧诱导的 RUNX2 抑制和 RANKL 合成。二甲双胍还抑制了低氧和 RANKL 增强的巨噬细胞中 TRAP 的合成。根管内二甲双胍减少了大鼠根尖周炎的骨丢失。与载体对照组相比，在二甲双胍治疗病变中衬于骨表面的细胞 RUNX2 表达明显增强，而 RANKL 和 TRAP 的合成减少。