Integrin alpha v beta 3 mediates the synergetic regulation of core-binding factor alpha 1 transcriptional activity by gravity and insulin-like growth factor-1 through phosphoinositide 3-kinase signaling

• Published in: Bone (New York, N.Y.) Vol. 69; pp. 126 - 132
• Main Authors: Dai, Zhongquan, Guo, Feima, Wu, Feng, Xu, Hongjie, Yang, Chao, Li, Jinqiao, Liang, Peilong, Zhang, Hongyu, Qu, Lina, Tan, Yingjun, Wan, Yumin, Li, Yinghui
• Format: Journal Article
• Language: English
• Published: 01.12.2014
• ISSN: 8756-3282
• DOI: 10.1016/j.bone.2014.09.018

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 alpha v beta 3 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 alpha 1 (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 alpha v beta 3 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 alpha v beta 3 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 beta 3 interacted with insulin receptor substrate 1, and that this interaction was decreased under SMG and increased under HG conditions. These results suggest that integrin alpha v beta 3 mediates the synergetic regulation of Cbfa1 transcription activity by gravity and IGF-1 via PI3K signaling.