mTORC2 signaling promotes skeletal growth and bone formation in mice

J Bone Miner Res. 2015 Feb;30(2):369-78. doi: 10.1002/jbmr.2348.

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.

Keywords: BONE; CARTILAGE; MECHANICAL LOADING; MOUSE; RICTOR; mTORC2.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Bone and Bones / embryology*
  • Cell Differentiation
  • Cell Proliferation
  • Chondrocytes / pathology
  • Embryo, Mammalian / physiology
  • Hypertrophy
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • Multiprotein Complexes / metabolism*
  • Osteoblasts / pathology
  • Osteogenesis*
  • Protein Biosynthesis
  • Signal Transduction*
  • Stress, Mechanical
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Multiprotein Complexes
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 2