mTORC1 Plays an Important Role in Skeletal Development by Controlling pre-Osteoblast Differentiation

Fitter, Stephen and Matthews, Mary P. and Martin, Sally K. and Xie, Jianling and Ooi, Soo Siang and Walkley, Carl R. and Codrington, John D. and Ruegg, Markus A. and Hall, Michael N. and Proud, Christopher G. and Gronthos, Stan and Zannettino, Andrew C. W.. (2017) mTORC1 Plays an Important Role in Skeletal Development by Controlling pre-Osteoblast Differentiation. Molecular and Cellular Biology, 37 (7). e00668-16.

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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 pre-osteoblasts 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 post-natal bone accrual, which was evident in skeletal elements derived from both intramembranous and endochondrial ossification. The decrease in bone accrual, and 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 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 pre-osteoblast differentiation.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
UniBasel Contributors:Hall, Michael N.
Item Type:Article, refereed
Publisher:American Society for Microbiology
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:09 Nov 2017 09:24
Deposited On:12 Oct 2017 08:32

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