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

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Abstract
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.