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A RANKL-based Osteoclast Culture Assay of Mouse Bone Marrow to Investigate the Role of mTORC1 in Osteoclast Formation
Published on: March 15, 2018
mTORC2 signaling promotes skeletal growth and bone formation in mice
Jianquan Chen1, Nilsson Holguin, Yu Shi
1Deaprtment of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA.
Abstract:
Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase controlling many physiological processes in mammals. mTOR functions in two distinct protein complexes, namely mTORC1 and mTORC2. Compared to mTORC1, the specific roles of mTORC2 are less well understood. To investigate the potential contribution of mTORC2 to skeletal development and homeostasis, we have genetically deleted Rictor, an essential component of mTORC2, in the limb skeletogenic mesenchyme of the mouse embryo. Loss of Rictor leads to shorter and narrower skeletal elements in both embryos and postnatal mice. In the embryo, Rictor deletion reduces the width but not the length of the initial cartilage anlage. Subsequently, the embryonic skeletal elements are shortened due to a delay in chondrocyte hypertrophy, with no change in proliferation, apoptosis, cell size, or matrix production. Postnatally, Rictor-deficient mice exhibit impaired bone formation, resulting in thinner cortical bone, but the trabecular bone mass is relatively normal thanks to a concurrent decrease in bone resorption. Moreover, Rictor-deficient bones exhibit a lesser anabolic response to mechanical loading. Thus, mTORC2 signaling is necessary for optimal skeletal growth and bone anabolism.
Insights
Mammalian target of rapamycin complex 2 (mTORC2) signaling is crucial for skeletal development. Genetic deletion of Rictor, an mTORC2 component, impairs bone growth and reduces anabolic responses to mechanical loading.
Area of Science:
- Cellular and Molecular Biology
- Skeletal Biology
- Biochemistry
Background:
- Mammalian target of rapamycin (mTOR) is a key regulator of cellular processes.
- mTOR functions via two complexes: mTORC1 and mTORC2.
- The precise roles of mTORC2 in skeletal homeostasis remain largely unelucidated.
Purpose of the Study:
- To investigate the function of mTORC2 in skeletal development and maintenance.
- To determine the impact of Rictor deletion on embryonic and postnatal skeletal elements.
Main Methods:
- Genetic deletion of Rictor, an essential mTORC2 component, in mouse embryonic limb skeletogenic mesenchyme.
- Analysis of skeletal morphology, chondrocyte differentiation, and bone formation in Rictor-deficient mice.
- Assessment of the response to mechanical loading in Rictor-deficient bones.
Main Results:
- Loss of Rictor resulted in shorter and narrower skeletal elements in embryos and postnatal mice.
- Rictor deletion delayed chondrocyte hypertrophy without affecting proliferation, apoptosis, or matrix production.
- Postnatal Rictor deficiency led to thinner cortical bone and reduced anabolic response to mechanical loading, with normal trabecular bone mass due to decreased resorption.
Conclusions:
- mTORC2 signaling, mediated by Rictor, is essential for normal skeletal growth and development.
- mTORC2 plays a critical role in regulating chondrocyte hypertrophy and bone formation.
- mTORC2 signaling is necessary for the anabolic response of bone to mechanical stimuli.
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