title: Inactivation of Regulatory-associated Protein of mTOR (Raptor)/Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in Osteoclasts Increases Bone Mass by Inhibiting Osteoclast Differentiation in Mice.
abstract: Mammalian target of rapamycin complex 1 (mTORC1) is involved in anabolic metabolism in both osteoblasts and chondrocytes, but the role of mTORC1 in osteoclast biology in vivo remains to be elucidated. In this study, we showed that deletion of regulatory-associated protein of mTOR (Raptor) in osteoclasts led to an increase in bone mass with decreased bone resorption. Raptor-deficient bone marrow-derived macrophages exhibited lower mTORC1-S6K1 signaling and retarded osteoclast differentiation, as determined by the number of osteoclasts, tartrate-resistant acid phosphatase activity, and expression of osteoclast-specific genes. Enforced expression of constitutively active S6K1 rescued the impaired osteoclast differentiation in Raptor-deficient bone marrow-derived macrophages. Furthermore, pharmacological inhibition of mTORC1 signaling by rapamycin could also inhibit osteoclast differentiation and osteoclast-specific gene expression. Taken together, our findings demonstrate that mTORC1 plays a key role in the network of catabolic bone resorption in osteoclasts and may serve as a potential pharmacological target for the regulation of osteoclast activity in bone metabolic disorders.
authors.affiliation: From the Departments of Pediatric Dentistry.|the State Key Laboratory of Cell Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Sciences, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Qinggang
authors.initials: Q
authors.lastname: Dai
authors.affiliation: From the Departments of Pediatric Dentistry.
authors.forename: Furong
authors.initials: F
authors.lastname: Xie
authors.affiliation: the State Key Laboratory of Cell Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Sciences, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yujiao
authors.initials: Y
authors.lastname: Han
authors.affiliation: Oral and Maxillofacial Head and Neck Oncology, and.
authors.forename: Xuhui
authors.initials: X
authors.lastname: Ma
authors.affiliation: Center of Craniofacial Orthodontics, Department of Oral and Craniomaxillofacial Science, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai 200011 and.
authors.forename: Siru
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Center of Craniofacial Orthodontics, Department of Oral and Craniomaxillofacial Science, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai 200011 and jly117@sina.com.
authors.forename: Lingyong
authors.initials: L
authors.lastname: Jiang
authors.affiliation: the State Key Laboratory of Cell Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Sciences, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China zouwg94@sibcb.ac.cn.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zou
authors.affiliation: From the Departments of Pediatric Dentistry, wangjun202@126.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D015519:Bone Density; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology*; D010012:Osteogenesis / Q000502:physiology*; D010766:Phosphorylation; D000076223:Regulatory-Associated Protein of mTOR; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D046912:Multiprotein Complexes; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: S6 kinase; bone; cell differentiation; mTOR complex (mTORC); osteoclast; osteoporosis