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mTORC1 Plays an Important Role in Skeletal Development by Controlling Preosteoblast 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 Preosteoblast Differentiation. Molecular and Cellular Biology, 37 (7). e00668-16.

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
UniBasel Contributors:Rüegg, Markus A. and Hall, Michael N.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Microbiology
ISSN:0270-7306
e-ISSN:1098-5549
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:05 Sep 2019 15:46
Deposited On:16 Oct 2017 10:04

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