mTORC1 Inhibits NF-κB/NFATc1 Signaling and Prevents Osteoclast Precursor Differentiation, In Vitro and In Mice.

The mechanistic target of rapamycin complex 1 (mTORC1) is a critical sensor for bone homeostasis and bone formation; however, the role of mTORC1 in osteoclast development and the underlying mechanisms have not yet been fully established. Here, we found that mTORC1 activity declined during osteoclast precursors differentiation in vitro and in vivo. We further targeted deletion of Raptor (mTORC1 key component) or Tsc1 (mTORC1 negative regulator) to constitutively inhibit or activate mTORC1 in osteoclast precursors (monocytes/macrophages), using LyzM-cre mice. Osteoclastic formation was drastically increased in cultures of Raptor deficient bone marrow monocytes/macrophages (BMMs), and Raptor-deficient mice displayed osteopenia with enhanced osteoclastogenesis. Conversely, BMMs lacking Tsc1 exhibited a severe defect in osteoclast-like differentiation and absorptive function, both of which were restored following rapamycin treatment. Importantly, expression of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), transcription factors that are essential for osteoclast differentiation was negatively regulated by mTORC1 in osteoclast lineages. These results provide evidence that mTORC1 plays as a critical role as an osteoclastic differentiation-limiting signal and suggest a potential drawback in treating bone loss-related diseases with mTOR inhibitors clinically.