mTORC1 plays an important role in skeletal development by controlling preosteoblast differentiation

Stephen Fitter, Mary P. Matthews, Sally K. Martin, Jianling Xie, Soo Siang Ooi, Carl R. Walkley, John D. Codrington, Markus A. Ruegg, Michael N. Hall, Christopher G. Proud, Stan Gronthos, Andrew C.W. Zannettino

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish
Article numbere00668-16
Number of pages20
JournalMolecular and Cellular Biology
Volume37
Issue number7
DOIs
Publication statusPublished - Jan 2017
Externally publishedYes

Keywords

  • MTORC1
  • Osteoblast
  • Osteogenesis
  • Raptor

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