Akiyama Toru, Bouillet Phillippe, Miyazaki Tsuyoshi, Kadono Yuho, Chikuda Hirotaka, Chung Ung-Il, Fukuda Akira, Hikita Atsuhiko, Seto Hiroaki, Okada Takashi, Inaba Toshiya, Sanjay Archana, Baron Roland, Kawaguchi Hiroshi, Oda Hiromi, Nakamura Kozo, Strasser Andreas, Tanaka Sakae
Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
EMBO J. 2003 Dec 15;22(24):6653-64. doi: 10.1093/emboj/cdg635.
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.
破骨细胞(OCs)在没有诸如巨噬细胞集落刺激因子(M-CSF)等营养因子的情况下会迅速发生凋亡。它们的凋亡与促凋亡的仅含BH3结构域的Bcl-2家族成员Bim的迅速且持续增加有关。这是由c-Cbl介导的Bim泛素化减少和蛋白酶体降解减少所致。尽管在bim-/-小鼠的骨骼组织中破骨细胞数量增加,但由于骨吸收减少,这些小鼠表现出轻度骨硬化。与bim+/+破骨细胞相比,从bim-/-动物的骨髓细胞分化而来的破骨细胞在没有M-CSF时存活时间显著延长,但bim-/-破骨细胞的骨吸收活性明显降低。在bim-/-细胞中过表达抗降解的无赖氨酸Bim突变体消除了M-CSF的抗凋亡作用,而野生型Bim则没有。这些结果表明,Bim水平的泛素化依赖性调节对于控制破骨细胞的凋亡和激活至关重要。