title: mTORC1 Plays an Important Role in Skeletal Development by Controlling Preosteoblast Differentiation.
abstract: The mammalian target of rapamycin complex 1 (mTORC1) is activated by extracellular factors that control bone accrual. However, the direct role of this complex in osteoblast biology remains to be determined. To investigate this question, we disrupted mTORC1 function in preosteoblasts by targeted deletion ofRaptor(Rptor) inOsterix-expressing cells. Deletion ofRptorresulted in reduced limb length that was associated with smaller epiphyseal growth plates in the postnatal skeleton.Rptordeletion caused a marked reduction in pre- and postnatal bone accrual, which was evident in skeletal elements derived from both intramembranous and endochondrial ossification. The decrease in bone accrual, as well as the associated increase in skeletal fragility, was due to a reduction in osteoblast function.In vitro, osteoblasts derived from knockout mice display a reduced osteogenic potential, and an assessment of bone-developmental markers inRptorknockout osteoblasts revealed a transcriptional profile consistent with an immature osteoblast phenotype suggesting that osteoblast differentiation was stalled early in osteogenesis. Metabolic labeling and an assessment of cell size ofRptorknockout osteoblasts revealed a significant decrease in protein synthesis, a major driver of cell growth. These findings demonstrate that mTORC1 plays an important role in skeletal development by regulating mRNA translation during preosteoblast differentiation.
authors.affiliation: Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Science, University of Adelaide, Adelaide, Australia stephen.fitter@adelaide.edu.au.|Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Fitter
authors.affiliation: Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Science, University of Adelaide, Adelaide, Australia.
authors.forename: Mary P
authors.initials: MP
authors.lastname: Matthews
authors.affiliation: Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Science, University of Adelaide, Adelaide, Australia.|Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, Australia.
authors.forename: Sally K
authors.initials: SK
authors.lastname: Martin
authors.affiliation: Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, Australia.
authors.forename: Jianling
authors.initials: J
authors.lastname: Xie
authors.affiliation: Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Science, University of Adelaide, Adelaide, Australia.|Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, Australia.
authors.forename: Soo Siang
authors.initials: SS
authors.lastname: Ooi
authors.affiliation: Stem Cell Regulation Unit, St Vincent's Institute of Medical Research, Melbourne, Victoria, Australia.
authors.forename: Carl R
authors.initials: CR
authors.lastname: Walkley
authors.affiliation: School of Mechanical Engineering, University of Adelaide, Adelaide, Australia.
authors.forename: John D
authors.initials: JD
authors.lastname: Codrington
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Ruegg
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
authors.affiliation: Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, Australia.|School of Biological Sciences, University of Adelaide, Adelaide, Australia.|Department of Biochemistry and Genetics, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Proud
authors.affiliation: Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia.|Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, Australia.
authors.forename: Stan
authors.initials: S
authors.lastname: Gronthos
authors.affiliation: Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Science, University of Adelaide, Adelaide, Australia.|Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, Australia.
authors.forename: Andrew C W
authors.initials: ACW
authors.lastname: Zannettino
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001846:Bone Development; D002454:Cell Differentiation; D017353:Gene Deletion; D006132:Growth Plate / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism*; D009929:Organ Size; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism*; D010641:Phenotype; D000076223:Regulatory-Associated Protein of mTOR; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014158:Transcription, Genetic
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: Raptor; mTORC1; osteoblast; osteogenesis