Proapoptotic Bcl-2 family member Bim plays an essential role in the osteoclast apoptosis and is degraded through ubiquitin/proteasome pathways in a caspase-3-dependent manner. This negative feedback loop in the Bim-caspase-3 axis is important for regulating the survival and activity of osteoclasts. Introduction: Bim is a member of the proapoptotic Bcl-2 family and regulates the mitochondrial apoptosis pathway. Bim expression is post-translationally regulated in osteoclasts (OCs) through ubiquitin/proteasome pathways, and Bim is critical for their survival and activity. Materials and Methods: Time-course of change in the expression of Bim in the course of OC apoptosis was examined, and the effect of various proteinase inhibitors on the degradation of Bim was analyzed. The role of caspase-3 and caspase-7 on Bim degradation was studied using RNA interference technique and caspase-3-/- mice. Results: Bim was degraded after caspase-3 activation, which was suppressed by a caspase inhibitor and a proteasome inhibitor. Bim degradation was suppressed by gene knockdown of caspase-3 or in caspase-3-/- OCs but not by caspase-7 knockdown. OCs generated from caspase-3-/- bone marrow cells exhibited a shorter life span and higher bone-resorbing activity than normal OCs. Association of Bim with E3 ubiquitin ligase c-Cbl was suppressed by gene knockdown of caspase-3 or in caspase-3-/- OCs. Actin ring formation and cathepsin K expression were promoted in caspase-3-/- OCs. Conclusions: Caspase-3 negatively regulates Bim expression by stimulating its degradation through ubiquitin/ proteasome pathways, thus creating a negative feedback loop in the Bim-caspase axis.
All Science Journal Classification (ASJC) codes
- Endocrinology, Diabetes and Metabolism
- Orthopedics and Sports Medicine