Regulation of Osteoclast Apoptosis by Bcl-2 Family Protein Bim and Caspase-3

  • Sakae Tanaka
  • Hidetoshi Wakeyama
  • Toru Akiyama
  • Katsuhiko Takahashi
  • Hitoshi Amano
  • Keiichi I. Nakayama
  • Kozo Nakamura
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 658)


Apopotosis of osteoclasts is regulated by the Bcl-2 family protein Bim. Bim is degraded in the course of osteoclast apoptosis, which is regulated by Caspase-3. Osteoclasts generated from caspase-3 –/– mice exhibited a shorter life span and a higher bone-resorbing activity than those generated from normal littermates. These results suggest the important role of Caspase-3-Bim axis in regulating both apoptosis and activation of osteoclasts.


Osteoclast Apoptosis Bim Caspase-3 



This work was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and the Health Science research grants from the Ministry of Health, Labor, and Welfare of Japan to S.T.


  1. 1.
    Akiyama, T., Bouillet, P., Miyazaki, T., Kadono, Y., Chikuda, H., Chung, U. I. et al. (2003). Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only Bcl-2 family member Bim. Embo J 22:6653–6664.CrossRefPubMedGoogle Scholar
  2. 2.
    Bouillet, P., Metcalf, D., Huang, D. C., Tarlinton, D. M., Kay, T. W., Kontgen, F. et al. (1999). Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286:1735–1738.CrossRefGoogle Scholar
  3. 3.
    Bouillet, P., Purton, J. F., Godfrey, D. I., Zhang, L. C., Coultas, L., Puthalakath, H. et al. (2002). -only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415:922–926.CrossRefPubMedGoogle Scholar
  4. 4.
    Gilley, J., Coffer, P. J., & Ham, J. (2003). FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. J Cell Biol 162:613–622.CrossRefPubMedGoogle Scholar
  5. 5.
    Huang, D. C., & Strasser, A. (2000). BH3-Only proteins-essential initiators of apoptotic cell death. Cell 103:839–842.CrossRefPubMedGoogle Scholar
  6. 6.
    Kerr, J. F., Wyllie, A. H., & Currie, A. R. (1972). Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257.PubMedGoogle Scholar
  7. 7.
    Ley, R., Balmanno, K., Hadfield, K., Weston, C. R., & Cook, S. J. (2003). Activation of the ERK1/2 signalling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein Bim. J Biol Chem 278:18811–18816.CrossRefPubMedGoogle Scholar
  8. 8.
    Meller, R., Cameron, J. A., Torrey, D. J., Clayton, C. E., Ordonez, A. N., Henshall, D. C. et al. (2006). Rapid degradation of Bim by the ubiquitin-proteasome pathway mediates short-term ischemic tolerance in cultured neurons. J Biol Chem 281:7429–7436.CrossRefPubMedGoogle Scholar
  9. 9.
    Miura, M., Chen, X. D., Allen, M. R., Bi, Y., Gronthos, S., Seo, B. M. et al. (2004). A crucial role of caspase-3 in osteogenic differentiation of bone marrow stromal stem cells. J Clin Invest 114:1704–1713.PubMedGoogle Scholar
  10. 10.
    Miyazaki, T., Katagiri, H., Kanegae, Y., Takayanagi, H., Sawada, Y., Yamamoto, A. et al (2000). Reciprocal role of ERK and NF-kappaB pathways in survival and activation of osteoclasts. J Cell Biol 148:333–342.CrossRefPubMedGoogle Scholar
  11. 11.
    Morishita, H., Makishima, T., Kaneko, C., Lee, Y. S., Segil, N., Takahashi, K. et al. (2001). Deafness due to degeneration of cochlear neurons in caspase-3-deficient mice. Biochem Biophys Res Commun 284:142–149.CrossRefPubMedGoogle Scholar
  12. 12.
    O‘Connor, L., Strasser, A., O‘Reilly, L. A., Hausmann, G., Admas, J. M., Cory, S. et al. (1998). Bim: a novel member of the Bcl-2 family that promotes apoptosis. Embo J 17: 384–395.CrossRefPubMedGoogle Scholar
  13. 13.
    Opferman, J. T., & Korsmeyer, S. J. (2003). Apoptosis in the development and maintenance of the immune system. Nat Immunol 4:410–415.CrossRefPubMedGoogle Scholar
  14. 14.
    Putcha, G. V., Moulder, K. L., Golden, J. P., Bouillet, P., Adams, J. A., Strasser, A. et al. (2001). Induction of BIM, a proapoptotic BH3-only BCL-2 family member, is critical for neuronal apoptosis. Neuron 29:615–628.CrossRefPubMedGoogle Scholar
  15. 15.
    Siegel, R. M. (2006). Caspases at the crossroads of immune-cell life and death. Nat Rev Immunol 6:308–317.CrossRefPubMedGoogle Scholar
  16. 16.
    Tanaka, S. (2007). Signaling axis in osteoclast biology and therapeutic targeting in the RANKL/RANK/OPG system. Am J Nephrol 27:466–478.CrossRefPubMedGoogle Scholar
  17. 17.
    Tanaka, S., Nakamura, I., Inoue, J., Oda, H., & Nakamura, K. (2003). Signal transduction pathways regulating osteoclast differentiation and function. J Bone Miner Metab 21:123–133.CrossRefPubMedGoogle Scholar
  18. 18.
    Tanaka, S., Nakamura, K., Takahasi, N., & Suda, T. (2005). Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system. Immunol Rev 208:30–49.CrossRefPubMedGoogle Scholar
  19. 19.
    Wakeyama, H., Akiyama, T., Kadono, Y., Nakamura, M., Oshima, Y., Nakamura, K. et al. (2007a). Posttranslational regulation of Bim by caspase-3. Ann N Y Acad Sci 1116:271–280.CrossRefPubMedGoogle Scholar
  20. 20.
    Wakeyama, H., Akiyama, T., Takahashi, K., Amano, H., Kadono, Y., Nakamura, M. et al. (2007b). Negative feedback loop in the Bim-caspase-3 axis regulating apoptosis and activity of osteoclasts. J Bone Miner Res 22:1631–1639.CrossRefPubMedGoogle Scholar
  21. 21.
    Wiggins, C. M., Band, H., & Cook, S. J. (2007). c-Cbl is not required for ERK1/2-dependent degradation of BimEL. Cell Signal 19:2605–2611.CrossRefPubMedGoogle Scholar
  22. 22.
    Wyllie, A. H., Kerr, J. F., & Currie, A. R. (1980). Cell death: the significance of apoptosis. Int Rev Cytol 68:251–306.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Sakae Tanaka
    • 1
  • Hidetoshi Wakeyama
    • 1
  • Toru Akiyama
    • 1
  • Katsuhiko Takahashi
    • 2
  • Hitoshi Amano
    • 3
  • Keiichi I. Nakayama
    • 4
  • Kozo Nakamura
    • 5
  1. 1.Department of Orthopaedic SurgeryFaculty of Medicine, The University of TokyoTokyoJapan
  2. 2.Department of Biological ChemistrySchool of Pharmaceutical Sciences, Showa UniversityTokyoJapan
  3. 3.Department of PharmacologySchool of Dentistry, Showa UniversityTokyoJapan
  4. 4.Department of Molecular and Cellular BiologyMedical Institute of Bioregulation, Kyushu UniversityFukuokaJapan
  5. 5.Department of Orthopaedic SurgeryFaculty of MedicineTokyoJapan

Personalised recommendations