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mTORC1 plays an important role in skeletal development by controlling preosteoblast differentiation
Fitter, Stephen Mathews, Mary P. Martin, Sally K. Xie, Jianling Ooi, Soo Siang Walkley, Carl Codrington, John D. Ruegg, Markus A. Hall, Michael N. Proud, Christopher G.
Fitter, Stephen
Mathews, Mary P.
Martin, Sally K.
Xie, Jianling
Ooi, Soo Siang
Walkley, Carl
Codrington, John D.
Ruegg, Markus A.
Hall, Michael N.
Proud, Christopher G.
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.
Keywords
Raptor, mTORC1, osteoblast, osteogenesis
Date
2017
Type
Journal article
Journal
Molecular and Cellular Biology
Book
Volume
37
Issue
7
Page Range
1-20
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Faculty of Health Sciences
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Relation URI
Source URL
Event URL
Open Access Status
License
File Access
Controlled