Open AccessOestrogen‐activated autophagy has a negative effect on the anti‐osteoclastogenic function of oestrogen
Author(s) -
Cheng Liang,
Zhu Yunrong,
Xie Denghui,
Ke Dianshan
Publication year - 2020
Publication title -
cell proliferation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.647
H-Index - 74
eISSN - 1365-2184
pISSN - 0960-7722
DOI - 10.1111/cpr.12789
Subject(s) - autophagy , osteoclast , rankl , activator (genetics) , in vivo , chemistry , estrogen , medicine , endocrinology , in vitro , microbiology and biotechnology , cancer research , pharmacology , receptor , apoptosis , biology , biochemistry
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 (17β‐estradiol) on osteoclastogenesis. Materials and methods After treatment with 17β‐estradiol in OCPs (from bone marrow‐derived macrophages, BMMs) and ovariectomy (OVX) mice, we measured the effect of 17β‐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 17β‐estradiol using autophagic inhibitor or knock‐down of autophagic genes. Results The results showed that direct administration of 17β‐estradiol enhanced the autophagic response of OCPs. Interestingly, 17β‐estradiol inhibited the stimulatory effect of receptor activator of nuclear factor‐κB ligand (RANKL) on the autophagy and osteoclastogenesis of OCPs. Moreover, 17β‐estradiol inhibited the downstream signalling of RANKL. Autophagic suppression by pharmacological inhibitors or gene silencing enhanced the inhibitory effect of 17β‐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 17β‐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.