Functional analysis of apoptosis-related proteins in osteoclasts

点击翻译按钮获取中文摘要

Homeostasis of the skeletal system is maintained by a bone remodeling process, which is dependent on a delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts. Osteoclasts are multinucleated giant cells primarily responsible for bone resorption, which rapidly underwent apoptosis after finishing their tasks. We have previously reported that proapoptotic Bcl-2 family molecule Bim played an essential role for apoptosis of osteoclasts, and moreover played a pivotal role on bone resorption activity of osteoclasts. However, the roles of anti-apoptotic molecule Bcl-2, Bcl-xL on survival and bone resorption activity of osteoclasts have not been fully elucidated. We therefore regarded Bcl-2 family molecules as the organic molecular complex, and generated bcl-2-/-, bcl-2-/- bim+/- mice, and bcl-x conditional knockout mice and analyzed the roles of the molecules on survival and bone resorption activity of osteoclasts. We demonstrated that anti-apoptotic molecule Bcl-2 and Bcl-xL promoted the survival of osteoclasts in ex vivo experiments. Remarkably, Bcl-xL suppressed the bone resorption activity of osteoclasts ; in contrast, Bcl-2 reasonably promoted the function of osteoclasts in ex vivo and in vivo experiments though they are the same anti-apoptotic Bcl-2 subfamily. The in vivo analysis of the role of bcl-2 deficiency in the skeletal tissue is hampered by the ill health and early death of bcl-2-/-mice. We therefore generated bcl-2-/- bim+/-mice in which a single bim allele was knocked out and represented that they grew normally into adults. We revealed that Bcl-2 was essential for maintaining normal bone homeostasis in the adult mice by analyzing bcl-2-/- bim+/-mice. Thus, Bcl-2 family proteins play pivotal roles on the function of respective cells in addition to regulation of their life and death.