The Unexpected Link Between Osteoclasts and the Immune System

  • Hiroshi TakayanagiEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 658)


Osteoimmunology is an interdisciplinary research field focused on the molecular understanding of the interplay of the skeletal and immune systems. In particular, the interaction between immune cells and osteoclasts is a current major topic of critical interest in this field. The macrophage-osteoclast interaction has long been studied, and the T-cellosteoclast interaction also attracted much attention in the study of arthritis. However, recent reports have revealed a hitherto unknown link between osteoclasts and other immune cells, including B cells and dendritic cells, suggesting a larger number of molecules are in fact shared by osteoclasts and immune cells. These findings will lead to a better understanding of the pathogenesis of diseases affecting both systems and may/will provide a molecular basis for novel therapeutic strategies.


Osteoclast T cells RANKL NFATc1 Cathepsin K 



This work was supported in part by Grant-in-Aid for Creative Scientific Research from the Japan Society for the Promotion of Science (JSPS); grants for the Genome Network Project and the Global Center of Excellence (GCOE) Program from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT); and grants from Tokyo Biochemical Research Foundation, Yokoyama Foundation for Clinical Pharmacology, the Japan Medical Association and Takeda Science Foundation.


  1. 1.
    Asagiri, M., Hirai, T., Kunigami, T. et al. (2008). Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis. Science, 319, 624–627CrossRefPubMedGoogle Scholar
  2. 2.
    Asagiri, M., Sato, K., Usami, T. et al. (2005). Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med, 202, 1261–1269CrossRefPubMedGoogle Scholar
  3. 3.
    Dewhirst, F.E., Stashenko, P.P., Mole, J.E. et al. (1985). Purification and partial sequence of human osteoclast-activating factor: identity with interleukin 1β. J Immunol 135, 2562–2568PubMedGoogle Scholar
  4. 4.
    Horton, J.E., Raisz, L.G., Simmons, H.A. et al. (1972). Bone resorbing activity in supernatant fluid from cultured human peripheral blood leukocytes. Science 177, 793–795CrossRefPubMedGoogle Scholar
  5. 5.
    Kaifu, T., Nakahara, J., Inui, M. et al. (2003). Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J Clin Invest 111, 323–332PubMedGoogle Scholar
  6. 6.
    Kim, N., Takami, M., Rho, J. et al. (2002). A novel member of the leukocyte receptor complex regulates osteoclast differentiation. J Exp Med 195, 201–209PubMedGoogle Scholar
  7. 7.
    Koga, T., Inui, M., Inoue, K. et al. (2004) Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428, 758–763CrossRefPubMedGoogle Scholar
  8. 8.
    Kong, Y.Y., Feige, U., Sarosi, I. et al. (1999). Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402, 304–309CrossRefPubMedGoogle Scholar
  9. 9.
    Mocsai, A., Humphrey, M.B., Van Ziffle, J.A. et al. (2004). The immunomodulatory adapter proteins DAP12 and Fc receptor-chain (FcR) regulate development of functional osteoclasts through the Syk tyrosine kinase. Proc Natl Acad Sci U S A 101, 6158–6163CrossRefPubMedGoogle Scholar
  10. 10.
    Mundy, G.R., Raisz, L.G., Cooper, R.A. et al. (1974). Evidence for the secretion of an osteoclast stimulating factor in myeloma. N Engl J Med 291, 1041–1046CrossRefPubMedGoogle Scholar
  11. 11.
    Sato, K., Suematsu, A., Nakashima, T. et al. (2006a). Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nat Med 12, 1410–1416CrossRefPubMedGoogle Scholar
  12. 12.
    Sato, K., Suematsu, A., Okamoto, K. et al. (2006b). Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med 203, 2673–2682CrossRefPubMedGoogle Scholar
  13. 13.
    Shinohara, M., Koga, T., Okamoto, K. et al. (2008). Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell 132, 794–806CrossRefPubMedGoogle Scholar
  14. 14.
    Takayanagi, H. (2007). Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol 7, 292–304CrossRefPubMedGoogle Scholar
  15. 15.
    Takayanagi, H., Kim, S., Koga, T. et al. (2002). Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling for terminal differentiation of osteoclasts. Dev Cell 3, 889–901CrossRefPubMedGoogle Scholar
  16. 16.
    Takayanagi, H., Ogasawara, K., Hida, S. et al. (2000). T cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-. Nature 408, 600–605CrossRefPubMedGoogle Scholar
  17. 17.
    Wagner, E.F., & Eferl, R. (2005). Fos/AP-1 proteins in bone and the immune system. Immunol Rev 208, 126–140CrossRefPubMedGoogle Scholar
  18. 18.
    Yamashita, T., Yao, Z., Li, F. et al. (2007). NF-κB p50 and p52 regulate receptor activator of NF-κB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. J Biol Chem 282, 18245–18253CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Cell SignalingGraduate School, Tokyo Medical and Dental UniversityTokyoJapan

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