自噬
兰克尔
细胞生物学
化学
程序性细胞死亡
体内
刺激
缺氧(环境)
骨质疏松症
铁蛋白
细胞凋亡
受体
生物
内分泌学
生物化学
氧气
激活剂(遗传学)
生物技术
有机化学
作者
Shuo Ni,Yuan Yin,Zhi Qian,Zeyuan Zhong,Tao Lv,Yanbin Kuang,Baoqing Yu
标识
DOI:10.1016/j.freeradbiomed.2021.04.027
摘要
Ferroptosis is a new form of regulated cell death. Several studies have demonstrated that ferroptosis was involved in multiple diseases. However, the precise role of ferroptosis in osteoporosis remains unclear. Here, we demonstrated that ferroptosis was involved in osteoclasts over the course of RANKL-induced differentiation, and it was induced by iron-starvation response and ferrintinophagy. Mechanistically, under normoxia but not hypoxia, ferroptosis could be induced due to iron-starvation response (increased transferrin receptor 1, decreased ferritin) followed by RANKL stimulation, and this was attributed to the down-regulation of aconitase activity. We further investigated intracellular iron homeostasis and found that ferritinophagy, a process initiated by FTH-NCOA4 complex autophagosome degradation, was activated followed by RANKL stimulation under normoxia. Interestingly, these processes could not be observed under hypoxia. Moreover, we demonstrated that HIF-1α contributed to the decrease of ferritinophagy and autophagy flux under hypoxia. Additionally, HIF-1α impair autophagy flux via inhibition of autophagosome formation under hypoxia in BMDMs. In vivo study, we indicated that HIF-1α specific inhibitor 2ME2 prevent OVX bone loss. In conclusion, our study comprehensively investigated the role of ferroptosis in osteoclasts in vitro and in vivo, and innovatively suggested that targeting HIF-1α and ferritin thus inducing ferroptosis in osteoclasts could be an alternative in treatment of osteoporosis.
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