mTORC1 impedes osteoclast differentiation via calcineurin and NFATc1

Area of Science:

• Molecular Biology
• Cell Biology
• Pharmacology
• Bone Biology

Background:

• Rapamycins are mTOR inhibitors used as immunosuppressants and anti-cancer agents.
• Clinical use of rapamycins is associated with bone complications like pain, necrosis, and high turnover.
• The underlying mechanisms linking rapamycin, mTOR signaling, and bone pathology remain poorly understood.

Purpose of the Study:

• To elucidate the role of mTORC1 signaling in osteoclast differentiation and function.
• To investigate the mechanistic basis for rapamycin-induced bone loss.
• To identify the signaling pathways mediating mTORC1 regulation during osteoclastogenesis.

Main Methods:

• Utilized loss-of-function (Raptor deletion) and gain-of-function (TSC1 deletion) genetic models in hematopoietic stem cells (HSCs) and osteoclast precursors.
• Administered rapamycin at low, clinically relevant doses to assess its effects on bone resorption.
• Investigated the molecular interplay between RANKL, calcineurin, mTORC1, and NFATc1 signaling pathways.

Main Results:

• mTORC1 activity is dynamically regulated during osteoclastogenesis, being high in precursors but downregulated by RANKL.
• Genetic manipulation of mTORC1 signaling demonstrated biphasic effects on osteoclastogenesis, dependent on the timing and level of inhibition/activation.
• Low-dose rapamycin treatment significantly enhanced osteoclast differentiation and bone resorption, leading to net bone loss.
• Discovered a novel signaling cascade where RANKL inactivates mTORC1 via calcineurin, subsequently activating NFATc1 through reduced phosphorylation.

Conclusions:

• mTORC1 plays a complex, biphasic role in regulating osteoclastogenesis.
• Clinically relevant doses of rapamycin can exacerbate bone loss by promoting osteoclast activity.
• A calcineurin-mTORC1-NFATc1 phosphorylation-dependent pathway is crucial for regulating osteoclast differentiation and bone turnover.