Dong Xian, Chen Shuo, He Yang, Zhang Yi
Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, PR China.
Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, PR China.
J Dent Sci. 2024 Oct;19(4):2106-2113. doi: 10.1016/j.jds.2024.05.003. Epub 2024 May 22.
BACKGROUND/PURPOSE: Medication-related osteonecrosis of the jaw (MRONJ) represents a rare yet serious adverse reaction associated with the prolonged use of anti-bone resorptive or anti-angiogenic agents. This study aimed to investigate the impact and underlying mechanisms of adipose-derived stem cells (ADSCs) in preventing MRONJ in a mouse model.
Following tooth extraction in MRONJ mice, ADSCs or PBS were administered via the tail vein. The healing progress of gingival epithelium and the extraction socket was assessed using a stereoscopic microscope and histological analysis. Immunofluorescence was employed to examine markers associated with autophagy (LC3 and SQSTM1) and apoptosis (Cleaved-CASP 3). Statistical analysis involved unpaired Student's t-test and ANOVA on ABI Prism 7500, with P-values below 0.05 deemed statistically significant.
ADSCs enhanced gingival epithelium migration and facilitated new bone formation. In the MRONJ group, the expressions of autophagy-related protein LC3 and SQSTM1 in gingival epithelium were concurrently elevated, which indicated autophagic flux was impaired. Conversely, when treated with ADSCs, the expression of LC3 and SQSTM1 were downregulated, similarly to the Control group. Mechanically, zoledronate induced a deficiency of autophagosome-lysosome fusion in epithelial cells, while ADSCs supernatant could promote the autolysosomes formation. Furthermore, ADSCs rescued the number of autophagy-related apoptotic cells in the gingival epithelium of MRONJ.
ADSCs could effectively prevent the occurrence of MRONJ, likely through the activation of autophagic flux and the inhibition of autophagy-related apoptosis in gingival epithelium. These findings enhanced the understanding of MRONJ pathogenesis and propose a potential therapeutic target for this disease.
背景/目的：药物相关性颌骨坏死（MRONJ）是一种与长期使用抗骨吸收或抗血管生成药物相关的罕见但严重的不良反应。本研究旨在探讨脂肪来源干细胞（ADSCs）在小鼠模型中预防MRONJ的作用及潜在机制。
对MRONJ小鼠拔牙后，经尾静脉注射ADSCs或PBS。使用立体显微镜和组织学分析评估牙龈上皮和拔牙创的愈合进程。采用免疫荧光法检测与自噬（LC3和SQSTM1）和凋亡（Cleaved-CASP 3）相关的标志物。统计分析采用ABI Prism 7500上的非配对学生t检验和方差分析，P值低于0.05被认为具有统计学意义。
ADSCs促进了牙龈上皮迁移并有助于新骨形成。在MRONJ组中，牙龈上皮中自噬相关蛋白LC3和SQSTM1的表达同时升高，这表明自噬流受损。相反，用ADSCs处理后，LC3和SQSTM1的表达下调，与对照组相似。机制上，唑来膦酸诱导上皮细胞自噬体-溶酶体融合缺陷，而ADSCs上清液可促进自溶酶体形成。此外，ADSCs挽救了MRONJ牙龈上皮中自噬相关凋亡细胞的数量。
ADSCs可能通过激活自噬流和抑制牙龈上皮中自噬相关凋亡来有效预防MRONJ的发生。这些发现加深了对MRONJ发病机制的理解，并为该疾病提出了一个潜在的治疗靶点。
