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Updated: Feb 27, 2026

A RANKL-based Osteoclast Culture Assay of Mouse Bone Marrow to Investigate the Role of mTORC1 in Osteoclast Formation
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mTOR/Raptor signaling is critical for skeletogenesis in mice through the regulation of Runx2 expression

Qinggang Dai1,2, Zhan Xu2, Xuhui Ma3

  • 1Department of Pediatric Dentistry, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University; Shanghai Key Laboratory of Stomatology, Shanghai 200011, China.

Cell Death and Differentiation
|July 8, 2017
PubMed

Insights

The mammalian target of rapamycin (mTOR)/regulatory-associated protein of mTOR (Raptor) pathway is crucial for bone formation. mTOR/Raptor signaling regulates runt-related transcription factor 2 (Runx2) expression, impacting skeletal development.

Area of Science:

  • Molecular Biology
  • Skeletal Biology
  • Cell Signaling

Background:

  • The mammalian target of rapamycin (mTOR)/regulatory-associated protein of mTOR (Raptor) pathway integrates growth factors, nutrients, and energy metabolism signals.
  • These signals are known to influence skeletal biology, but the specific role of mTOR/Raptor in osteoblast biology in vivo is debated.

Purpose of the Study:

  • To elucidate the in vivo role of the mTOR/Raptor pathway in osteoblast biology.
  • To investigate the molecular mechanisms by which mTOR/Raptor signaling affects bone formation.

Main Methods:

  • Generation of mice with deficiencies in mTOR or Raptor in preosteoblasts.
  • Analysis of skeletal phenotypes, including clavicular hypoplasia and fontanelle fusion.
  • Mechanistic studies involving estrogen receptor α (ERα), Distal-less homeobox 5 (DLX5), and runt-related transcription factor 2 (Runx2) expression and activity.

Main Results:

  • Mice lacking mTOR or Raptor in preosteoblasts displayed clavicular hypoplasia and delayed fontanelle fusion, mimicking cleidocranial dysplasia (CCD).
  • The mTOR-Raptor-S6K1 axis was found to regulate Runx2 expression via ERα phosphorylation, influencing Runx2 enhancer activity.
  • Genetic interaction between Raptor and Runx2 was observed, with Raptor deficiency exacerbating bone defects in Runx2+/- mice.

Conclusions:

  • mTOR/Raptor signaling is essential for in vivo bone formation by regulating Runx2 expression.
  • These findings highlight a critical role for mTOR/Raptor in skeletal development.
  • Selective mTOR/Raptor antagonists might pose a risk of bone loss as a side effect.

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