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mTORC1 Plays an Important Role in Skeletal Development by Controlling Preosteoblast Differentiation

  • Fitter, Stephen Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, Australia
  • Matthews, Mary P. Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Science, University of Adelaide, Adelaide, Australia
  • Martin, Sally K. Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, Australia
  • Xie, Jianling Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, Australia
  • Ooi, Soo Siang Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, Australia
  • Walkley, Carl R. Stem Cell Regulation Unit, St Vincent's Institute of Medical Research, Melbourne, Victoria, Australia
  • Codrington, John D. School of Mechanical Engineering, University of Adelaide, Adelaide, Australia
  • Ruegg, Markus A. Biozentrum, University of Basel, Basel, Switzerland
  • Hall, Michael N. Biozentrum, University of Basel, Basel, Switzerland
  • Proud, Christopher G. Department of Biochemistry and Genetics, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China
  • Gronthos, Stan Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, Australia
  • Zannettino, Andrew C. W. Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, Australia
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  • 2017-3-17
Published in:
  • Molecular and Cellular Biology. - American Society for Microbiology. - 2017, vol. 37, no. 7
Cell Biology
Molecular Biology
English 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 of Raptor (Rptor) in Osterix-expressing cells. Deletion of Rptor resulted in reduced limb length that was associated with smaller epiphyseal growth plates in the postnatal skeleton. Rptor deletion 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 in Rptor knockout 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 of Rptor knockout 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.
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  • English
Open access status
bronze
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https://sonar.ch/global/documents/231700
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