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, China.
First Clinical Division, Peking University School Hospital of Stomatology, Beijing, China.
Autophagy. 2023 Nov;19(11):2899-2911. doi: 10.1080/15548627.2023.2234228. Epub 2023 Jul 21.
Macroautophagy/autophagy has both negative and positive aspects in the development of many diseases. Yet, its exact role and specific mechanism in the onset of medication-related osteonecrosis of the jaw (MRONJ) is still not fully understood. Retarded gingiva healing is the primary clinical manifestation in patients with MRONJ. In this study, we aimed to explore the relationship between autophagy and apoptosis in MRONJ gingival epithelium and search for a method to prevent this disease. First, we examined clinical samples from patients diagnosed with MRONJ and healthy controls, finding that autophagy-related markers MAP1LC3/LC3 and SQSTM1/p62 synchronously increased, thus suggesting that autophagic flux was suppressed in MRONJ. Moreover, mRNA sequencing analysis and TUNEL assay showed that the process of apoptosis was upregulated in patients and animals with MRONJ, indicating autophagy and apoptosis participate in the development of MRONJ. Furthermore, the level of autophagy and apoptosis in zoledronic acid (ZA)-treated human keratinocytes cell lines (HaCaT cells) was concentration dependent . In addition, we also found that RAB7 (RAB7, member RAS oncogene family) activator ML098 could rescue MRONJ gingival lesions in mice by activating the autophagic flux and downregulating apoptosis. To sum up, this study demonstrated that autophagic flux is impaired in the gingival epithelium during MRONJ, and the rescued autophagic flux could prevent the occurrence of MRONJ. ACTB: actin beta; Baf-A1: bafilomycin A; CASP3: caspase 3; CASP8: caspase 8; CT: computed tomography; DMSO: dimethyl sulfoxide; GFP: green fluorescent protein; HaCaT cells: human keratinocytes cell lines; H&E: hematoxylin and eosin; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MRONJ: medication-related osteonecrosis of the jaw; PARP: poly(ADP-ribose) polymerase; RAB7: RAB7, member RAS oncogene family; RFP: red fluorescent protein; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; ZA: zoledronic acid.
自噬/自噬在许多疾病的发展中既有负面也有正面影响。然而，其在药物相关性颌骨坏死（MRONJ）发病中的确切作用和具体机制尚不完全清楚。牙龈愈合延迟是 MRONJ 患者的主要临床表现。在本研究中，我们旨在探讨自噬与 MRONJ 牙龈上皮细胞凋亡之间的关系，并寻找预防这种疾病的方法。首先，我们检查了诊断为 MRONJ 的患者和健康对照的临床样本，发现自噬相关标志物 MAP1LC3/LC3 和 SQSTM1/p62 同步增加，这表明 MRONJ 中自噬流受到抑制。此外，mRNA 测序分析和 TUNEL 检测表明，MRONJ 患者和动物的凋亡过程上调，表明自噬和凋亡参与了 MRONJ 的发生。此外，唑来膦酸（ZA）处理的人角质形成细胞系（HaCaT 细胞）中自噬和凋亡的水平呈浓度依赖性。此外，我们还发现 RAB7（RAB7，RAS 癌基因家族成员）激活剂 ML098 可以通过激活自噬流和下调凋亡来挽救 MRONJ 小鼠的牙龈病变。总之，本研究表明，MRONJ 时牙龈上皮的自噬流受损，挽救的自噬流可以预防 MRONJ 的发生。ACTB：肌动蛋白β；Baf-A1：巴佛洛霉素 A；CASP3：半胱天冬酶 3；CASP8：半胱天冬酶 8；CT：计算机断层扫描；DMSO：二甲基亚砜；GFP：绿色荧光蛋白；HaCaT 细胞：人角质形成细胞系；H&E：苏木精和伊红；MAP1LC3/LC3：微管相关蛋白 1 轻链 3；MRONJ：药物相关性颌骨坏死；PARP：多聚（ADP-核糖）聚合酶；RAB7：RAB7，RAS 癌基因家族成员；RFP：红色荧光蛋白；SQSTM1/p62：自噬体相关蛋白 1；TEM：透射电子显微镜；ZA：唑来膦酸。
