Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only Bcl-2 family member Bim.
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.
Akiyama
Toru
T
Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Bouillet
Phillippe
P
Miyazaki
Tsuyoshi
T
Kadono
Yuho
Y
Chikuda
Hirotaka
H
Chung
Ung-Il
UI
Fukuda
Akira
A
Hikita
Atsuhiko
A
Seto
Hiroaki
H
Okada
Takashi
T
Inaba
Toshiya
T
Sanjay
Archana
A
Baron
Roland
R
Kawaguchi
Hiroshi
H
Oda
Hiromi
H
Nakamura
Kozo
K
Strasser
Andreas
A
Tanaka
Sakae
S
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000235:genetics*; D006706:Homeostasis; D017403:In Situ Hybridization; D008297:Male; D008565:Membrane Proteins; D008682:Metatarsal Bones / Q000166:cytology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology* / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D025801:Ubiquitin / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D002352:Carrier Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D025801:Ubiquitin