Oestrogen-activated autophagy has a negative effect on the anti-osteoclastogenic function of oestrogen
Oestrogen-activated autophagy has a negative effect on the anti-osteoclastogenic function of oestrogen
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雌激素激活的自噬对雌激素的抗破骨细胞功能有负面影响
DOI：
10.1111/cpr.12789
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发表时间：
2020-04-01
影响因子：
8.5
通讯作者：
Xie, Denghui
中科院分区：
文献类型：
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作者：
Cheng, Liang;Zhu, Yunrong;Xie, Denghui
雌激素被认为可以抑制破骨细胞的形成，许多研究已经确定它是一种自噬激活剂。迄今为止，雌激素在破骨细胞发生过程中破骨细胞前体（OCPs）自噬中的作用尚不清楚。本研究旨在确定生物活性形式的雌激素（17 β -雌二醇）调节的自噬对破骨细胞发生的影响。材料与方法用17 β -雌二醇处理ocp（来自骨髓源性巨噬细胞，BMMs）和卵巢切除（OVX）小鼠，在体外和体内测量17 β -雌二醇对ocp自噬的影响。此外，我们通过自噬抑制剂或敲除自噬基因，研究了自噬在17 β -雌二醇调控OCP增殖、破骨细胞分化和骨质流失中的作用。结果直接给药17 -雌二醇可增强ocp的自噬反应。有趣的是，17 -雌二醇抑制了核因子- κ B配体受体激活剂（RANKL）对ocp自噬和破骨细胞发生的刺激作用。此外，17 -雌二醇抑制RANKL的下游信号传导。通过药物抑制剂或基因沉默抑制自噬增强了17 β -雌二醇对破骨细胞发生的抑制作用。体内实验表明，自噬抑制剂3-MA不仅能抑制OVX小鼠小梁骨ocp的自噬活性，还能增强17 -雌二醇改善骨质流失的能力。综上所述，我们的研究表明，雌激素直接增强OCPs的自噬，从而抑制其抗破骨作用。基于自噬抑制的药物可提高雌激素治疗骨质疏松症的疗效。
Objectives Oestrogen is known to inhibit osteoclastogenesis, and numerous studies have identified it as an autophagic activator. To date, the role of oestrogen in the autophagy of osteoclast precursors (OCPs) during osteoclastogenesis remains unclear. This study aimed to determine the effect of autophagy regulated by the biologically active form of oestrogen (17 beta-estradiol) on osteoclastogenesis.Materials and methods After treatment with 17 beta-estradiol in OCPs (from bone marrow-derived macrophages, BMMs) and ovariectomy (OVX) mice, we measured the effect of 17 beta-estradiol on the autophagy of OCPs in vitro and in vivo. In addition, we studied the role of autophagy in the OCP proliferation, osteoclast differentiation and bone loss regulated by 17 beta-estradiol using autophagic inhibitor or knock-down of autophagic genes.Results The results showed that direct administration of 17 beta-estradiol enhanced the autophagic response of OCPs. Interestingly, 17 beta-estradiol inhibited the stimulatory effect of receptor activator of nuclear factor-kappa B ligand (RANKL) on the autophagy and osteoclastogenesis of OCPs. Moreover, 17 beta-estradiol inhibited the downstream signalling of RANKL. Autophagic suppression by pharmacological inhibitors or gene silencing enhanced the inhibitory effect of 17 beta-estradiol on osteoclastogenesis. In vivo assays showed that the autophagic inhibitor 3-MA not only inhibited the autophagic activity of the OCPs in the trabecular bone of OVX mice but also enhanced the ability of 17 beta-estradiol to ameliorate bone loss.Conclusions In conclusion, our study showed that oestrogen directly enhanced the autophagy of OCPs, which inhibited its anti-osteoclastogenic effect. Drugs based on autophagic inhibition may enhance the efficacy of oestrogen on osteoporosis.