Frontiers in Pharmacology (Jun 2019)

mTORC1 Activation in Osteoclasts Prevents Bone Loss in a Mouse Model of Osteoporosis

  • Manami Hiraiwa,
  • Kakeru Ozaki,
  • Takanori Yamada,
  • Takashi Iezaki,
  • Takashi Iezaki,
  • Gyujin Park,
  • Kazuya Fukasawa,
  • Tetsuhiro Horie,
  • Hikari Kamada,
  • Kazuya Tokumura,
  • Mei Motono,
  • Katsuyuki Kaneda,
  • Eiichi Hinoi

DOI
https://doi.org/10.3389/fphar.2019.00684
Journal volume & issue
Vol. 10

Abstract

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The mechanistic/mammalian target of rapamycin (mTOR) is widely implicated in the pathogenesis of various diseases, including cancer, obesity, and cardiovascular disease. Bone homeostasis is maintained by the actions of bone-resorbing osteoclasts and bone-forming osteoblasts. An imbalance in the sophisticated regulation of osteoclasts and osteoblasts leads to the pathogenesis as well as etiology of certain metabolic bone diseases, including osteoporosis and osteopetrosis. Here, we identified mTOR complex 1 (mTORC1) as a pivotal mediator in the regulation of bone resorption and bone homeostasis under pathological conditions through its expression in osteoclasts. The activity of mTORC1, which was indicated by the phosphorylation level of its downstream target p70S6 kinase, was reduced during osteoclast differentiation, in accordance with the upregulation of Hamartin (encoded by tuberous sclerosis complex 1 [Tsc1]), a negative regulator of mTORC1. Receptor activator of nuclear factor-κB ligand (RANKL)-dependent osteoclastogenesis was impaired in Tsc1-deficient bone marrow macrophages. By contrast, osteoclastogenesis was markedly enhanced by Raptor deficiency but was unaffected by Rictor deficiency. The deletion of Tsc1 in osteoclast lineage cells in mice prevented bone resorption and bone loss in a RANKL-induced mouse model of osteoporosis, although neither bone volume nor osteoclastic parameter was markedly altered in these knockout mice under physiological conditions. Therefore, these findings suggest that mTORC1 is a key potential target for the treatment of bone diseases.

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