Feng Chong, Liu Yan, Zhang Bao-Yi, Zhang Hao, Shan Fa-Yu, Li Tian-Qi, Zhao Zhi-Ning, Wang Xin-Xing, Zhang Xiang-Yu
School and Hospital of Stomatology, Tianjin Medical University, Tianjin 300070, China.
Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
ACS Omega. 2023 May 29;8(23):20739-20754. doi: 10.1021/acsomega.3c01289. eCollection 2023 Jun 13.
Periodontitis is a progressive inflammatory skeletal disease characterized by periodontal tissue destruction, alveolar bone resorption, and tooth loss. Chronic inflammatory response and excessive osteoclastogenesis play essential roles in periodontitis progression. Unfortunately, the pathogenesis that contributes to periodontitis remains unclear. As a specific inhibitor of the mTOR (mammalian/mechanistic target of rapamycin) signaling pathway and the most common autophagy activator, rapamycin plays a vital role in regulating various cellular processes. The present study investigated the effects of rapamycin on osteoclast (OC) formation in vitro and its effects on the rat periodontitis model. The results showed that rapamycin inhibited OC formation in a dose-dependent manner by up-regulating the Nrf2/GCLC signaling pathway, thus suppressing the intracellular redox status, as measured by 2',7'-dichlorofluorescein diacetate and MitoSOX. In addition, rather than simply increasing the autophagosome formation, rapamycin increased the autophagy flux during OC formation. Importantly, the anti-oxidative effect of rapamycin was regulated by an increase in autophagy flux, which could be attenuated by blocking autophagy with bafilomycin A1. In line with the in vitro results, rapamycin treatment attenuated alveolar bone resorption in rats with lipopolysaccharide-induced periodontitis in a dose-dependent manner, as assessed by micro-computed tomography, hematoxylin-eosin staining, and tartrate-resistant acid phosphatase staining. Besides, high-dose rapamycin treatment could reduce the serum levels of proinflammatory factors and oxidative stress in periodontitis rats. In conclusion, this study expanded our understanding of rapamycin's role in OC formation and protection from inflammatory bone diseases.
牙周炎是一种进行性炎症性骨骼疾病，其特征为牙周组织破坏、牙槽骨吸收和牙齿脱落。慢性炎症反应和过度的破骨细胞生成在牙周炎进展中起重要作用。不幸的是，导致牙周炎的发病机制仍不清楚。作为哺乳动物雷帕霉素靶蛋白（mTOR）信号通路的特异性抑制剂和最常见的自噬激活剂，雷帕霉素在调节各种细胞过程中起着至关重要的作用。本研究调查了雷帕霉素对体外破骨细胞（OC）形成的影响及其对大鼠牙周炎模型的作用。结果表明，雷帕霉素通过上调Nrf2/GCLC信号通路以剂量依赖性方式抑制OC形成，从而抑制细胞内氧化还原状态，这通过二乙酸2',7'-二氯荧光素和MitoSOX进行测定。此外，雷帕霉素并非简单地增加自噬体形成，而是在OC形成过程中增加自噬通量。重要的是，雷帕霉素的抗氧化作用通过自噬通量的增加来调节，而用巴弗洛霉素A1阻断自噬可使其减弱。与体外结果一致，通过显微计算机断层扫描、苏木精-伊红染色和抗酒石酸酸性磷酸酶染色评估，雷帕霉素治疗以剂量依赖性方式减轻了脂多糖诱导的大鼠牙周炎中的牙槽骨吸收。此外，高剂量雷帕霉素治疗可降低牙周炎大鼠的促炎因子血清水平和氧化应激。总之，本研究扩展了我们对雷帕霉素在OC形成和预防炎性骨疾病中作用的理解。
