title: Evidence of the Role of R-Spondin 1 and Its Receptor Lgr4 in the Transmission of Mechanical Stimuli to Biological Signals for Bone Formation.
abstract: The bone can adjust its mass and architecture to mechanical stimuli via a series of molecular cascades, which have been not yet fully elucidated. Emerging evidence indicated that R-spondins (Rspos), a family of secreted agonists of the Wnt/β-catenin signaling pathway, had important roles in osteoblastic differentiation and bone formation. However, the role of Rspo proteins in mechanical loading-influenced bone metabolism has never been investigated. In this study, we found that Rspo1 was a mechanosensitive protein for bone formation. Continuous cyclic mechanical stretch (CMS) upregulated the expression of Rspo1 in mouse bone marrow mesenchymal stem cells (BMSCs), while the expression of Rspo1 in BMSCs in vivo was downregulated in the bones of a mechanical unloading mouse model (tail suspension (TS)). On the other hand, Rspo1 could promote osteogenesis of BMSCs under CMS through activating the Wnt/β-catenin signaling pathway and could rescue the bone loss induced by mechanical unloading in the TS mice. Specifically, our results suggested that Rspo1 and its receptor of leucine-rich repeat containing G-protein-coupled receptor 4 (Lgr4) should be a novel molecular signal in the transmission of mechanical stimuli to biological signal in the bone, and this signal should be in the upstream of Wnt/β-catenin signaling for bone formation. Rspo1/Lgr4 could be a new potential target for the prevention and treatment of disuse osteoporosis in the future.
authors.affiliation: Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. shiguixun@163.com.
authors.forename: Gui-Xun
authors.initials: GX
authors.lastname: Shi
authors.affiliation: Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. zxf272@126.com.
authors.forename: Xin-Feng
authors.initials: XF
authors.lastname: Zheng
authors.affiliation: Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. chaozhu007@126.com.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. libo6275819@126.com.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. 13564869748@163.com.
authors.forename: Yu-Ren
authors.initials: YR
authors.lastname: Wang
authors.affiliation: Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. jiangsd@126.com.
authors.forename: Sheng-Dan
authors.initials: SD
authors.lastname: Jiang
authors.affiliation: Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. jiangleisheng@xinhuamed.com.cn.
authors.forename: Lei-Sheng
authors.initials: LS
authors.lastname: Jiang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D005786:Gene Expression Regulation; D040542:Mechanotransduction, Cellular; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D010012:Osteogenesis; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D013314:Stress, Mechanical; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: C496200:LGR4 protein, mouse; C518903:RSPO1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D019699:Thrombospondins
keywords: Lgr4; R-spondin 1; bone formation; bone mechanotransduction; osteoporosis