Rictor/mTORC2 Loss in Osteoblasts Impairs Bone Mass and Strength

Bone. 2016 Sep;90:50-8. doi: 10.1016/j.bone.2016.05.010. Epub 2016 Jun 2.

Abstract

Mammalian target of rapamycin (mTOR) is a Ser/Thr kinase conserved through evolution that coordinates extra cellular signals associated with cell growth. Main functions of mTOR present in the form of two complexes, namely mTORC1 and mTORC2, which are distinct in their unique components, raptor and rictor. In the current study, using a Cre/loxp system, we found an anabolic effect of mTORC2 signaling on skeleton. Osteoblast differentiation was reduced, with down-regulation of mTORC2 signaling activity in primary cultures of osteoblasts that did not contain rictor. Mice with a specific deletion of rictor in mature osteoblasts showed a significant reduction in lean mass and bone mineral density by dual energy x-ray absorptiometry analysis. Micro-computed tomography, histomorphometric, and molecular biological analyses revealed a marked impairment of the cortical bone mass and microarchitecture, as well as minor changes in trabecular bone, of the Rictorob(-/-) mice. Cortical bone mass and thickness of the femoral mid-shaft were dramatically reduced, with unusual increases in porosity and marrow area in Rictorob(-/-) mice. Thinner trabeculae were found in the L4 vertebrae with relatively normal structural indices of trabecular numbers and separation. A lower rate of bone turnover was observed, as the consequence of the decreased individual osteoblast activity and bone resorption. Furthermore, these changes were associated with significantly decreased bone biomechanical properties. In conclusion, expression of rictor in osteoblasts is essential for the maintenance of normal bone remodeling and microarchitecture, especially for the maintenance of the cortical bone.

Keywords: Bone remodeling; Osteoblasts; Osteoclasts; Rictor; mTORC2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / metabolism
  • Animals
  • Biomechanical Phenomena
  • Bone Resorption / diagnostic imaging
  • Bone Resorption / pathology
  • Bone Resorption / physiopathology
  • Bone and Bones / diagnostic imaging
  • Bone and Bones / pathology*
  • Bone and Bones / physiopathology*
  • Cancellous Bone / pathology
  • Cell Differentiation
  • Cells, Cultured
  • Cortical Bone / pathology
  • Femur / diagnostic imaging
  • Femur / pathology
  • Femur / physiopathology
  • Gene Deletion
  • Integrases / metabolism
  • Mechanistic Target of Rapamycin Complex 2 / metabolism*
  • Mice, Inbred C57BL
  • Organ Size
  • Osteoblasts / metabolism*
  • Osteoblasts / pathology*
  • Rapamycin-Insensitive Companion of mTOR Protein / deficiency
  • Rapamycin-Insensitive Companion of mTOR Protein / metabolism*
  • Signal Transduction
  • X-Ray Microtomography

Substances

  • Rapamycin-Insensitive Companion of mTOR Protein
  • rictor protein, mouse
  • Mechanistic Target of Rapamycin Complex 2
  • Cre recombinase
  • Integrases