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  • The EMBO Journal (2003) 22, 6653 - 6664
  • doi:10.1093/emboj/cdg635

Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only Bcl-2 family member Bim

Toru Akiyama1, Phillippe Bouillet2, Tsuyoshi Miyazaki1, Yuho Kadono1, Hirotaka Chikuda1, Ung-il Chung1, Akira Fukuda1, Atsuhiko Hikita1, Hiroaki Seto3, Takashi Okada4, Toshiya Inaba5, Archana Sanjay6, Roland Baron6, Hiroshi Kawaguchi1, Hiromi Oda1, Kozo Nakamura1, Andreas Strasser2 and Sakae Tanaka1

  1. Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
  2. The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3050 Victoria, Australia
  3. Department of Orthopaedics, Juntendo University, School of Medicine, Minamikawachi, Kawachi, Tochigi 329-0498, Japan
  4. Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical School, 3311-1 Yakushiji, Minamikawachi, Kawachi, Tochigi 329-0498, Japan
  5. Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan
  6. Departments of Cell Biology and Orthopaedics, Yale University School of Medicine, New Haven, CT, USA

Correspondence to:

Sakae Tanaka, E-mail: TANAKAS-ORT@h.u-tokyo.ac.jp

Received 10 June 2003; Accepted 30 October 2003; Revised 27 October 2003

Osteoclasts (OCs) undergo rapid apoptosis without trophic factors, such as macrophage colony-stimulating factor (M-CSF). Their apoptosis was associated with a rapid and sustained increase in the pro-apoptotic BH3-only Bcl-2 family member Bim. This was caused by the reduced ubiquitylation and proteasomal degradation of Bim that is mediated by c-Cbl. Although the number of OCs was increased in the skeletal tissues of bim-/- mice, the mice exhibited mild osteosclerosis due to reduced bone resorption. OCs differentiated from bone marrow cells of bim-/- animals showed a marked prolongation of survival in the absence of M-CSF, compared with bim+/+ OCs, but the bone-resorbing activity of bim-/- OCs was significantly reduced. Overexpression of a degradation-resistant lysine-free Bim mutant in bim-/- cells abrogated the anti-apoptotic effect of M-CSF, while wild-type Bim did not. These results demonstrate that ubiquitylation-dependent regulation of Bim levels is critical for controlling apoptosis and activation of OCs.

  • Keywords:

    • apoptosis,
    • bim,
    • M-CSF,
    • osteoclast,
    • ubiquitylation