title: mTORC1 Prevents Preosteoblast Differentiation through the Notch Signaling Pathway.
abstract: The mechanistic target of rapamycin (mTOR) integrates both intracellular and extracellular signals to regulate cell growth and metabolism. However, the role of mTOR signaling in osteoblast differentiation and bone formation is undefined, and the underlying mechanisms have not been elucidated. Here, we report that activation of mTOR complex 1 (mTORC1) is required for preosteoblast proliferation; however, inactivation of mTORC1 is essential for their differentiation and maturation. Inhibition of mTORC1 prevented preosteoblast proliferation, but enhanced their differentiation in vitro and in mice. Activation of mTORC1 by deletion of tuberous sclerosis 1 (Tsc1) in preosteoblasts produced immature woven bone in mice due to excess proliferation but impaired differentiation and maturation of the cells. The mTORC1-specific inhibitor, rapamycin, restored these in vitro and in vivo phenotypic changes. Mechanistically, mTORC1 prevented osteoblast maturation through activation of the STAT3/p63/Jagged/Notch pathway and downregulation of Runx2. Preosteoblasts with hyperactive mTORC1 reacquired the capacity to fully differentiate and maturate when subjected to inhibition of the Notch pathway. Together, these findings identified the role of mTORC1 in osteoblast formation and established that mTORC1 prevents preosteoblast differentiation and maturation through activation of the Notch pathway.
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Huang
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Yongkui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China.
authors.forename: Pinglin
authors.initials: P
authors.lastname: Lai
authors.affiliation: Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yan
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China; Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China.
authors.forename: Song
authors.initials: S
authors.lastname: Xu
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Limin
authors.initials: L
authors.lastname: Rong
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: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Daozhang
authors.initials: D
authors.lastname: Cai
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Dadi
authors.initials: D
authors.lastname: Jin
authors.affiliation: Academy of Orthopedics, Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China; Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, China.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Bai
mesh_terms: D000818:Animals; D001848:Bone Diseases, Developmental / Q000000981:diagnostic imaging / Q000473:pathology; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D000076222:Mechanistic Target of Rapamycin Complex 1; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000502:physiology*; D010006:Osteoblasts / Q000187:drug effects / Q000502:physiology*; D011859:Radiography; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D046912:Multiprotein Complexes; D051880:Receptors, Notch; C493716:Runx2 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus