title: Activation of mTORC1 in B Lymphocytes Promotes Osteoclast Formation via Regulation of β-Catenin and RANKL/OPG.
abstract: The cytokine receptor activator of nuclear factor-κB ligand (RANKL) induces osteoclast formation from monocyte/macrophage lineage cells. However, the mechanisms by which RANKL expression is controlled in cells that support osteoclast differentiation are still unclear. We show that deletion of TSC1 (tuberous sclerosis complex 1) in murine B cells causes constitutive activation of mechanistic target of rapamycin complex 1 (mTORC1) and stimulates RANKL but represses osteoprotegerin (OPG) expression and subsequently promotes osteoclast formation and causes osteoporosis in mice. Furthermore, the regulation of RANKL/OPG and stimulation of osteoclastogenesis by mTORC1 was confirmed in a variety of RANKL-expressing cells and in vivo. Mechanistically, mTORC1 controls RANKL/OPG expression through negative feedback inactivation of Akt, destabilization of β-catenin mRNA, and downregulation of β-catenin. Our findings demonstrate that mTORC1 activation-stimulated RANKL expression in B cells is sufficient to induce bone loss and osteoporosis. The study also established a link between mTORC1 and the RANKL/OPG axis via negative regulation of β-catenin. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.|Academy of Orthopedics in Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Song
authors.initials: S
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.|Academy of Orthopedics in Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.affiliation: Academy of Orthopedics in Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Huang
authors.affiliation: Academy of Orthopedics in Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yan
authors.affiliation: Academy of Orthopedics in Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Kangyan
authors.initials: K
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Jia
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lin
authors.affiliation: Academy of Orthopedics in Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Academy of Orthopedics in Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Daozhang
authors.initials: D
authors.lastname: Cai
authors.affiliation: Academy of Orthopedics in Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Dadi
authors.initials: D
authors.lastname: Jin
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.|Academy of Orthopedics in Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Bai
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D053244:Osteoprotegerin; D053245:RANK Ligand; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D051176:beta Catenin; D000076222:Mechanistic Target of Rapamycin Complex 1
keywords: B LYMPHOCYTE; OSTEOCLAST FORMATION; RANKL (RECEPTOR ACTIVATOR OF NUCLEAR FACTOR-κB LIGAND); mTORC1 (MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1); β-CATENIN