mTORC1 impedes osteoclast differentiation via calcineurin and NFATc1

Hoang Dinh Huynh, Yihong Wan

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Rapamycins are immunosuppressant and anti-cancer drugs that inhibit the kinase mTOR. Clinically, they often cause bone pain, bone necrosis, and high bone turnover, yet the mechanisms are unclear. Here we show that mTORC1 activity is high in osteoclast precursors but downregulated upon RANKL treatment. Loss-of-function genetic models reveal that while early Raptor deletion in hematopoietic stem cells blunts osteoclastogenesis due to compromised proliferation/survival, late Raptor deletion in osteoclast precursors instead augments osteoclastogenesis. Gain-of-function genetic models by TSC1 deletion in HSCs or osteoclast precursors cause constitutive mTORC1 activation, impairing osteoclastogenesis. Pharmacologically, rapamycin treatment at low but clinically relevant doses exacerbates osteoclast differentiation and bone resorption, leading to bone loss. Mechanistically, RANKL inactivates mTORC1 via calcineurin-mediated mTORC1 dephosphorylation, consequently activating NFATc1 by reducing mTORC1-mediated NFATc1 phosphorylation. These findings uncover biphasic roles of mTORC1 in osteoclastogenesis, dosage-dependent effects of rapamycin on bone, and a previously unrecognized calcineurin–mTORC1–NFATc1 phosphorylation-regulatory signaling cascade.

Original languageEnglish (US)
Article number29
JournalCommunications Biology
Volume1
Issue number1
DOIs
StatePublished - Dec 1 2018

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osteoclasts
Calcineurin
Osteoclasts
Bone
bones
Osteogenesis
Sirolimus
Raptors
birds of prey
Phosphorylation
Genetic Models
phosphorylation
Bone and Bones
immunosuppressive agents
bone resorption
dephosphorylation
antineoplastic agents
dosage
Osteonecrosis
Bone Remodeling

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Medicine (miscellaneous)

Cite this

mTORC1 impedes osteoclast differentiation via calcineurin and NFATc1. / Huynh, Hoang Dinh; Wan, Yihong.

In: Communications Biology, Vol. 1, No. 1, 29, 01.12.2018.

Research output: Contribution to journalArticle

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