FTO-associated osteoclastogenesis promotes alveolar bone resorption in apical periodontitis male rat via the HK1/USP14/RANK pathway
Yajie Qian, Jing Wu, Weidong Yang, Ruining Lyu, Qiao You, Jingjing Li, Qin He, Yuan Zhuang, Wenmei Wang, Yong Wang, Yanan Zhu, Zhiwei Wu, Deyan Chen
Abstract
Alveolar bone resorption (ABR) is a key pathological manifestation in the development of apical periodontitis (AP) and contributes to the AP-associated tooth loss among AP patients in the clinic. However, the underlying mechanism of ABR development is largely unknown. Here we show, the total levels of N6-methyladenosine (m6A) were reduced in AP male rat alveolar bone tissues and BMDM-derived osteoclasts (OC), which was associated with the up-regulation of obesity-associated protein (FTO). Subsequently FTO-mediated hexokinase (HK1) demethylation modification enhancing glycolytic pathway that stabilizes receptor activator of NF-κB (RANK) protein via the deubiquitination activity of ubiquitin-specific protease 14 (USP14), which further promotes osteoclastogenesis to participate in the AP-related ABR development. Finally, Dac51 (an FTO inhibitor) and 2-DG (an HK1 inhibitor) both exhibit the inhibitory activity of osteoclastogenesis. Our current study reveals a molecular mechanism on osteoclastogenesis-related ABR and provides a therapeutic target of AP via modulating the FTO/HK1/USP14/RANK axis. Alveolar bone resorption (ABR) is a key pathological manifestation in the development of apical periodontitis (AP) that contributes to the AP-associated tooth loss, and whose underlying mechanism is largely unknown. Here, the authors show a molecular mechanism on osteoclastogenesis-related ABR and provides a therapeutic target of AP via modulating the FTO/HK1/USP14/RANK axis.