title: Glucocorticoids: Dose-related effects on osteoclast formation and function via reactive oxygen species and autophagy.
abstract: Whether glucocorticoids directly enhance or interrupt osteoclastogenesis is still a controversial subject. In this study, we ascertained the dose-dependent positive effects of glucocorticoids on osteoclastogenesis in vivo and in vitro as well as investigated the mechanism in vitro. As the dose of glucocorticoids increased, osteoclastogenesis was stimulated at 0.1 μM, a peak was achieved at 1 μM and a corresponding decrease occurred at 10 μM. Reactive oxygen species (ROS), which play a crucial role in osteoclastogenesis, and autophagy flux activity, a cellular recycling process, were consistently up-regulated along with the dose-dependent effects of the glucocorticoids on osteoclast formation and function. N-acetyl-cysteine (NAC), a ROS scavenger, abrogated the effects of the glucocorticoids on autophagy and osteoclastogenesis. Moreover, 3-methyladenine (3-MA), an autophagy inhibitor, interrupted osteoclastogenesis stimulation by the glucocorticoids. These results implied that with glucocorticoid administration, ROS and autophagy, as a downstream factor of ROS, played vital roles in osteoclast formation and function. 3-MA administration did not enhance ROS accumulation, so that autophagy had no effect on ROS induced by glucocorticoids. Our investigation demonstrated that glucocorticoids had dose-dependent positive effects on osteoclast formation and function via ROS and autophagy. These results provide support for ROS and autophagy as therapeutic targets in glucocorticoid-related bone loss diseases such as glucocorticoid-induced osteoporosis.
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Shi
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Jie
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Li
authors.affiliation: Institute of Orthopedics, Xi'an Chinese Medicine Hospital, China.
authors.forename: Qiyue
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Gao
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Yuehu
authors.initials: Y
authors.lastname: Han
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Guo
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, China. Electronic address: ljreny@fmmu.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, China. Electronic address: yangliu@fmmu.edu.cn.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Institute of Orthopedics, Xijing Hospital, Fourth Military Medical University, China. Electronic address: zjluofmmu@hotmail.com.
authors.forename: Zhuojing
authors.initials: Z
authors.lastname: Luo
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D055114:X-Ray Microtomography
chemical_list: D005938:Glucocorticoids; D017382:Reactive Oxygen Species
keywords: Autophagy; Glucocorticoids; Osteoclast; Osteoclast precursors; Reactive oxygen species