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mTORC1 Plays an Important Role in Skeletal Development by Controlling Preosteoblast Differentiation
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
ID
3851142
Author(s)
Fitter, Stephen; Matthews, Mary P.; Martin, Sally K.; Xie, Jianling; Ooi, Soo Siang; Walkley, Carl R.; Codrington, John D.; Ruegg, Markus A.; Hall, Michael N.; Proud, Christopher G.; Gronthos, Stan; Zannettino, Andrew C. W.
mTORC1 Plays an Important Role in Skeletal Development by Controlling Preosteoblast Differentiation
Journal
Molecular and Cellular Biology
Volume
37
Number
7
Pages / Article-Number
e00668-16
Keywords
Raptor, mTORC1, osteoblast, osteogenesis
Mesh terms
Adaptor Proteins, Signal Transducing, metabolism; Adipose Tissue, metabolism; Animals; Animals, Newborn; Bone Development; Cell Differentiation; Gene Deletion; Growth Plate, metabolism; Mechanistic Target of Rapamycin Complex 1; Mice, Transgenic; Multiprotein Complexes, metabolism; Organ Size; Osteoblasts, metabolism; Phenotype; Regulatory-Associated Protein of mTOR; TOR Serine-Threonine Kinases, metabolism; Transcription, Genetic
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.
