title: Dose-response estrogen promotes osteogenic differentiation via GPR40 (FFAR1) in murine BMMSCs.
abstract: Estrogen plays an essential role in bone formation, and estrogen modulation dysfunction is tightly associated with postmenopausal osteoporosis (PMOP). The underlying mechanisms of estrogen-mediated osteogenic differentiation have not been well defined. In this study, murine bone marrow mesenchymal stem cells were induced to undergo osteogenic differentiation, and gene expression analysis or GPR40 expression manipulation was performed. Bilateral ovariectomized or sham-operated C57BL/6 mice were administered GPR40 agonist (GW9508) for bone mineral density analysis. We identified GPR40, a long chain unsaturated fatty acid receptor, to be regulated by estrogen and involved in osteogenic differentiation both in vivo and in vitro. Mechanistically, the Wnt/β-catenin signaling pathway is essential for GPR40 to promote osteogenic differentiation. Furthermore, in vivo GW9508 administration rescued estrogen-deficient bone loss, indicating the essential role of the GPR40 receptor. To our knowledge, this is the first study that provides evidence for GPR40 as a positive regulator of osteogenesis and Wnt/β-catenin signaling. These results indicate that GPR40 may function as an endogenous promoter of estrogen-induced osteogenic differentiation through Wnt/β-catenin signaling activation. Therefore, as the global population of ages and the prevalence of metabolic-related disorders, especially PMOP, increases, our findings suggest that GPR40 is a key in understanding the link between bone and fat. It may also be a useful target for the treatment of bone complications in the future.
authors.affiliation: Department of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Gao
authors.affiliation: Department of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Jie
authors.affiliation: Department of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China.
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China.
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Zhang
authors.affiliation: Department of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China. Electronic address: liujianhq@sina.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China. Electronic address: yangliufmmu@gmail.com.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China. Electronic address: zjluo@fmmu.edu.cn.
authors.forename: Zhuo-Jing
authors.initials: ZJ
authors.lastname: Luo
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis / Q000187:drug effects*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
chemical_list: D004967:Estrogens; C473036:Ffar1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: BMMSCs; Estrogen; GPR40; Osteogenesis; PMOP