The Role of mTOR in Osteoclasts

  • Ralph A. Zirngibl
  • Irina VoronovEmail author
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)


Evolutionary conserved kinase mechanistic target of rapamycin (mTOR) is the signaling hub for cellular responses to nutrients, cytokines, growth hormones, and environmental stresses in all eukaryotic cells. Increased mTOR activity has been demonstrated in numerous diseases, such as cancer and autoimmune diseases. Due to its prominent role, mTOR inhibitors are being used and tested to treat a wide variety of conditions. Recent evidence suggests that regulation of mTOR activity and function is not universal and varies between the cells. Here we summarize the latest research on the role and regulation of mTOR in osteoclasts, the unique multinucleated bone-resorbing cells, focusing on the role of mTOR as part of the mTORC1 complex. Collectively, the results suggest that mTORC1 activity plays a double role in osteoclastogenesis: at the earlier stage, it is necessary for proliferation of the precursors, and, at the later stage, it is indispensable for cytoskeletal reorganization involved in the process of bone resorption. We also present evidence that in osteoclasts, mTOR protein levels and activity are regulated differently compared to other primary cells and cell lines. Due to this prominent role of mTOR in osteoclast formation and function, mTOR inhibitors could be used to treat numerous diseases that involve overactive osteoclasts, such as osteoporosis, inflammatory arthritis, Paget’s disease, and cancer-related osteolysis.


mTOR Osteoclast Lysosome V-ATPase Bone 


  1. 1.
    Crockett JC, et al. Bone remodelling at a glance. J Cell Sci. 2011;124(Pt 7):991–8.CrossRefGoogle Scholar
  2. 2.
    Teti A. Mechanisms of osteoclast-dependent bone formation. Bonekey Rep. 2013;2:449.CrossRefPubMedGoogle Scholar
  3. 3.
    Ono T, Nakashima T. Recent advances in osteoclast biology. Histochem Cell Biol. 2018;149:325.CrossRefGoogle Scholar
  4. 4.
    Kong YY, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999;397(6717):315–23.CrossRefGoogle Scholar
  5. 5.
    Hsu H, et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci U S A. 1999;96(7):3540–5.CrossRefPubMedGoogle Scholar
  6. 6.
    Wiktor-Jedrzejczak W, et al. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci U S A. 1990;87(12):4828–32.CrossRefPubMedGoogle Scholar
  7. 7.
    Salo J, et al. Removal of osteoclast bone resorption products by transcytosis. Science. 1997;276(5310):270–3.CrossRefGoogle Scholar
  8. 8.
    Tondravi MM, et al. Osteopetrosis in mice lacking haematopoietic transcription factor PU.1. Nature. 1997;386(6620):81–4.CrossRefGoogle Scholar
  9. 9.
    Carey HA, et al. Enhancer variants reveal a conserved transcription factor network governed by PU.1 during osteoclast differentiation. Bone Res. 2018;6:8.CrossRefPubMedGoogle Scholar
  10. 10.
    Yagi M, et al. DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells. J Exp Med. 2005;202(3):345–51.CrossRefPubMedGoogle Scholar
  11. 11.
    Miyamoto H, et al. OC-STAMP and DC-STAMP cooperatively modulate cell-cell fusion to form osteoclasts and foreign body giant cells. J Bone Miner Res. 2012;27:1289.CrossRefGoogle Scholar
  12. 12.
    McDonald M, et al. Intravital imaging of osteoclasts in vivo reveals cellular recycling as a novel cell fate mechanism. J Bone Miner Res. 2017;32(Suppl 1):Abstrac #1109.Google Scholar
  13. 13.
    Clausen BE, et al. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 1999;8(4):265–77.CrossRefGoogle Scholar
  14. 14.
    Chiu WS, et al. Transgenic mice that express Cre recombinase in osteoclasts. Genesis. 2004;39(3):178–85.CrossRefGoogle Scholar
  15. 15.
    Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168(6):960–76.CrossRefPubMedGoogle Scholar
  16. 16.
    Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science. 1991;253(5022):905–9.CrossRefGoogle Scholar
  17. 17.
    Hara K, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002;110(2):177–89.CrossRefGoogle Scholar
  18. 18.
    Nojima H, et al. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J Biol Chem. 2003;278(18):15461–4.CrossRefGoogle Scholar
  19. 19.
    Kim DH, et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell. 2003;11(4):895–904.CrossRefGoogle Scholar
  20. 20.
    Peterson TR, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009;137(5):873–86.CrossRefPubMedGoogle Scholar
  21. 21.
    Sancak Y, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell. 2007;25(6):903–15.CrossRefGoogle Scholar
  22. 22.
    Laplante M, Sabatini DM. Regulation of mTORC1 and its impact on gene expression at a glance. J Cell Sci. 2013;126(Pt 8):1713–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Betz C, Hall MN. Where is mTOR and what is it doing there? J Cell Biol. 2013;203(4):563–74.CrossRefPubMedGoogle Scholar
  24. 24.
    Meng D, Frank AR, Jewell JL. mTOR signaling in stem and progenitor cells. Development. 2018;145(1):pii: dev152595.CrossRefGoogle Scholar
  25. 25.
    Efeyan A, Zoncu R, Sabatini DM. Amino acids and mTORC1: from lysosomes to disease. Trends Mol Med. 2012;18(9):524–33.CrossRefPubMedGoogle Scholar
  26. 26.
    Manning BD, et al. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell. 2002;10(1):151–62.CrossRefGoogle Scholar
  27. 27.
    Han S, et al. Pam (Protein associated with Myc) functions as an E3 ubiquitin ligase and regulates TSC/mTOR signaling. Cell Signal. 2008;20(6):1084–91.CrossRefPubMedGoogle Scholar
  28. 28.
    Wolfson RL, Sabatini DM. The dawn of the age of amino acid sensors for the mTORC1 pathway. Cell Metab. 2017;26(2):301–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Sancak Y, et al. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010;141(2):290–303.CrossRefPubMedGoogle Scholar
  30. 30.
    Zoncu R, et al. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science. 2011;334(6056):678–83.CrossRefPubMedGoogle Scholar
  31. 31.
    Wang S, et al. Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science. 2015;347(6218):188–94.CrossRefPubMedGoogle Scholar
  32. 32.
    Rebsamen M, et al. SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature. 2015;519(7544):477–81.CrossRefPubMedGoogle Scholar
  33. 33.
    Chantranupong L, et al. The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell. 2016;165(1):153–64.CrossRefPubMedGoogle Scholar
  34. 34.
    Saxton RA, et al. Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science. 2016;351(6268):53–8.CrossRefGoogle Scholar
  35. 35.
    Wolfson RL, et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science. 2016;351(6268):43–8.CrossRefGoogle Scholar
  36. 36.
    Shen HM, Mizushima N. At the end of the autophagic road: an emerging understanding of lysosomal functions in autophagy. Trends Biochem Sci. 2014;39(2):61–71.CrossRefGoogle Scholar
  37. 37.
    Halova L, et al. Phosphorylation of the TOR ATP binding domain by AGC kinase constitutes a novel mode of TOR inhibition. J Cell Biol. 2013;203(4):595–604.CrossRefPubMedGoogle Scholar
  38. 38.
    Perl A. Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases. Nat Rev Rheumatol. 2016;12(3):169–82.CrossRefGoogle Scholar
  39. 39.
    Indo Y, et al. Metabolic regulation of osteoclast differentiation and function. J Bone Miner Res. 2013;28(11):2392–9.CrossRefGoogle Scholar
  40. 40.
    Zhang Y, et al. mTORC1 inhibits NF-kappaB/NFATc1 signaling and prevents osteoclast precursor differentiation, in vitro and in mice. J Bone Miner Res. 2017;32(9):1829–40.CrossRefGoogle Scholar
  41. 41.
    Xu S, et al. TSC1 regulates osteoclast podosome organization and bone resorption through mTORC1 and Rac1/Cdc42. Cell Death Differ. 2018;Google Scholar
  42. 42.
    Glantschnig H, et al. M-CSF, TNFalpha and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase. Cell Death Differ. 2003;10(10):1165–77.CrossRefGoogle Scholar
  43. 43.
    Sugatani T, Hruska KA. Akt1/Akt2 and mammalian target of rapamycin/Bim play critical roles in osteoclast differentiation and survival, respectively, whereas Akt is dispensable for cell survival in isolated osteoclast precursors. J Biol Chem. 2005;280(5):3583–9.CrossRefGoogle Scholar
  44. 44.
    Hussein O, et al. Rapamycin inhibits osteolysis and improves survival in a model of experimental bone metastases. Cancer Lett. 2012;314(2):176–84.CrossRefGoogle Scholar
  45. 45.
    Wu H, et al. Bone size and quality regulation: concerted actions of mTOR in mesenchymal stromal cells and osteoclasts. Stem Cell Rep. 2017;8(6):1600–16.CrossRefGoogle Scholar
  46. 46.
    Touaitahuata H, Blangy A, Vives V. Modulation of osteoclast differentiation and bone resorption by Rho GTPases. Small GTPases. 2014;5:e28119.CrossRefPubMedGoogle Scholar
  47. 47.
    Dai Q, et al. Inactivation of regulatory-associated protein of mTOR (raptor)/mammalian target of rapamycin complex 1 (mTORC1) signaling in osteoclasts increases bone mass by inhibiting osteoclast differentiation in mice. J Biol Chem. 2017;292(1):196–204.CrossRefGoogle Scholar
  48. 48.
    Tiedemann K, et al. Regulation of osteoclast growth and fusion by mTOR/raptor and mTOR/rictor/Akt. Front Cell Dev Biol. 2017;5:54.CrossRefPubMedGoogle Scholar
  49. 49.
    Noda T, Ohsumi Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem. 1998;273(7):3963–6.CrossRefGoogle Scholar
  50. 50.
    Korolchuk VI, et al. Lysosomal positioning coordinates cellular nutrient responses. Nat Cell Biol. 2011;13(4):453–60.CrossRefPubMedGoogle Scholar
  51. 51.
    Puertollano R. mTOR and lysosome regulation. F1000Prime Rep. 2014;6:52.CrossRefPubMedGoogle Scholar
  52. 52.
    Rabanal-Ruiz Y, Korolchuk VI. mTORC1 and Nutrient homeostasis: the central role of the lysosome. Int J Mol Sci. 2018;19(3):pii: E818.CrossRefGoogle Scholar
  53. 53.
    Sardiello M, et al. A gene network regulating lysosomal biogenesis and function. Science. 2009;325(5939):473–7.CrossRefGoogle Scholar
  54. 54.
    Kawasaki-Nishi S, Nishi T, Forgac M. Arg-735 of the 100-kDa subunit a of the yeast V-ATPase is essential for proton translocation. Proc Natl Acad Sci U S A. 2001;98(22):12397–402.CrossRefPubMedGoogle Scholar
  55. 55.
    Voronov I, et al. The R740S mutation in the V-ATPase a3 subunit increases lysosomal pH, impairs NFATc1 translocation, and decreases in vitro osteoclastogenesis. J Bone Miner Res. 2013;28(1):108–18.CrossRefGoogle Scholar
  56. 56.
    Ochotny N, et al. The V-ATPase a3 subunit mutation R740S is dominant negative and results in osteopetrosis in mice. J Bone Miner Res. 2011;26(7):1484–93.CrossRefGoogle Scholar
  57. 57.
    Toyomura T, et al. Three subunit a isoforms of mouse vacuolar H(+)-ATPase. Preferential expression of the a3 isoform during osteoclast differentiation. J Biol Chem. 2000;275(12):8760–5.CrossRefGoogle Scholar
  58. 58.
    Manolson MF, et al. The a3 isoform of the 100-kDa V-ATPase subunit is highly but differentially expressed in large (>or=10 nuclei) and small (<or= nuclei) osteoclasts. J Biol Chem. 2003;278(49):49271–8.CrossRefGoogle Scholar
  59. 59.
    Ochotny N, et al. The R740S mutation in the V-ATPase a3 subunit results in osteoclast apoptosis and defective early-stage autophagy. J Cell Biochem. 2013;114(12):2823–33.CrossRefGoogle Scholar
  60. 60.
    Johnson L, et al. V-ATPases containing a3 subunit play a direct role in enamel development in mice. J Cell Biochem. 2017;118(10):3328–40.CrossRefGoogle Scholar
  61. 61.
    Liu H, et al. Degradation of regulator of calcineurin 1 (RCAN1) is mediated by both chaperone-mediated autophagy and ubiquitin proteasome pathways. FASEB J. 2009;23(10):3383–92.CrossRefGoogle Scholar
  62. 62.
    Hu Y, et al. Lysosomal pH plays a key role in regulation of mTOR activity in osteoclasts. J Cell Biochem. 2016;117(2):413–25.CrossRefGoogle Scholar
  63. 63.
    Wang A, et al. Activity-independent targeting of mTOR to lysosomes in primary osteoclasts. Sci Rep. 2017;7(1):3005.CrossRefPubMedGoogle Scholar
  64. 64.
    Bartolomeo R, et al. mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy. J Clin Invest. 2017;127(10):3717–29.CrossRefPubMedGoogle Scholar
  65. 65.
    Newton PT, et al. Pharmacological inhibition of lysosomes activates the MTORC1 signaling pathway in chondrocytes in an autophagy-independent manner. Autophagy. 2015;11(9):1594–607.CrossRefPubMedGoogle Scholar
  66. 66.
    Hwang JY, et al. Global ischemia induces lysosomal-mediated degradation of mTOR and activation of autophagy in hippocampal neurons destined to die. Cell Death Differ. 2017;24:317.CrossRefGoogle Scholar
  67. 67.
    Johnson DE, et al. The position of lysosomes within the cell determines their luminal pH. J Cell Biol. 2016;212(6):677–92.CrossRefPubMedGoogle Scholar
  68. 68.
    Heuser J. Changes in lysosome shape and distribution correlated with changes in cytoplasmic pH. J Cell Biol. 1989;108(3):855–64.CrossRefGoogle Scholar
  69. 69.
    Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423(6937):337–42.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Faculty of DentistryUniversity of TorontoTorontoCanada

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