Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only Bcl-2 family member Bim
Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only Bcl-2 family member Bim
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DOI：
10.1093/emboj/cdg635
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发表时间：
2003-12-15
期刊：
影响因子：
11.4
通讯作者：
Tanaka, S
中科院分区：
文献类型：
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作者：
Akiyama, T;Bouillet, P;Tanaka, S
破骨细胞（OCs）在没有营养因子如巨噬细胞集落刺激因子（M-CSF）的情况下经历快速凋亡。它们的凋亡与促凋亡BH 3-only Bcl-2家族成员Bim的快速和持续增加相关。这是由c-Cbl介导的Bim的泛素化和蛋白酶体降解减少引起的。尽管bim-/-小鼠骨骼组织中OC的数量增加，但由于骨吸收减少，小鼠表现出轻度骨质疏松。与bim+/+ OCs相比，从bim-/-动物骨髓细胞分化的OCs在没有M-CSF的情况下显示出明显的存活延长，但bim-/- OCs的骨吸收活性显著降低。在bim-/-细胞中过表达抗降解的无赖氨酸Bim突变体废除了M-CSF的抗凋亡作用，而野生型Bim没有。这些结果表明，Bim水平的泛素化依赖性调节对于控制OC的凋亡和活化至关重要。
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.