title: Integrin αvβ3 mediates the synergetic regulation of core-binding factor α1 transcriptional activity by gravity and insulin-like growth factor-1 through phosphoinositide 3-kinase signaling.
abstract: Mechanical stimulation and biological factors coordinately regulate bone development and regeneration; however, the underlying mechanisms are poorly understood. Microgravity induces bone loss, which may be partly related to the development of resistance to local cytokines, including insulin-like growth factor 1 (IGF-1). Here, we report the involvement of integrin αvβ3 in microgravity-associated bone loss. An established OSE-3T3 cell model was stably transfected with a 6OSE2 (Osteoblast-Specific Element 2)-luciferase reporter and cultured under simulated microgravity (SMG) and hypergravity (HG) conditions in the presence or absence of IGF-1, the disintegrin echistatin, the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, or combinations of these agents. Activity of core-binding factor α1 (Cbfa1), an essential transcription factor for osteoblastic differentiation and osteogenesis, was reflected by luciferase activity. Different gravity conditions affected the induction of IGF-1 and subsequent effects on Cbfa1 transcription activity. SMG and HG influenced the expression and activity of integrin αvβ3 and phosphorylation level of p85. LY294002 inhibited the effects of HG or IGF-1 on Cbfa1 activity, indicating that HG and IGF-1 could increase Cbfa1 activity via PI3K signaling. Inhibition of integrin αvβ3 by echistatin attenuated the induction of IGF-1 and thus its effect on Cbfa1 activity under normal and HG conditions. Co-immunoprecipitation demonstrated that integrin β3 interacted with insulin receptor substrate 1, and that this interaction was decreased under SMG and increased under HG conditions. These results suggest that integrin αvβ3 mediates the synergetic regulation of Cbfa1 transcription activity by gravity and IGF-1 via PI3K signaling.
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China. Electronic address: daizhq77@163.com.
authors.forename: Zhongquan
authors.initials: Z
authors.lastname: Dai
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China. Electronic address: guofeima@126.com.
authors.forename: Feima
authors.initials: F
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China. Electronic address: wufeng1984221@163.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China. Electronic address: xuhongjie316@163.com.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China. Electronic address: Zhangxiuyc@163.com.
authors.forename: Chao
authors.initials: C
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China. Electronic address: Iverson12@126.com.
authors.forename: Jinqiao
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China. Electronic address: 359691154@qq.com.
authors.forename: Peilong
authors.initials: P
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China. Electronic address: hongyu_zhang1@163.com.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China. Electronic address: linaqu@263.com.
authors.forename: Lina
authors.initials: L
authors.lastname: Qu
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China. Electronic address: tyj1@163.com.
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China. Electronic address: spacefisher@126.com.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Wan
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China. Electronic address: yinghuidd@vip.sina.com.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Li
mesh_terms: D016475:3T3 Cells; D000818:Animals; D015153:Blotting, Western; D016723:Bone Remodeling / Q000502:physiology; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D018470:Gravity, Altered / Q000009:adverse effects*; D047468:Immunoprecipitation; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013026:Space Flight; D014162:Transfection; D014893:Weightlessness / Q000009:adverse effects
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D039302:Integrin alphaVbeta3; D034741:RNA, Small Interfering; C493716:Runx2 protein, mouse; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases
keywords: Bone loss; Cbfa1; Gravity; IGF-1; Integrin αvβ3; Synergetic regulation