Regulation of osteoblastic differentiation by the ubiquitin-proteasome pathway and novel induction of bone formation

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Recent observations suggest that bone metabolism is regulated by the ubiquitin-proteasome pathway, and certain proteasome inhibitor has been reported to induce differentiation of osteoblasts in vitro and in vivo. In this study, we show that bortezomib induces osteoblastic differentiation and inhibits myogenic differentiation in C2C12 cells in culture. Bortezomib inhibits ubiquitin proteasome pathway to degradation of osteogenic transcriptional factor Runx2 and the function of proteasome in controlling degradation of signaling molecules in osteoblast differentiation. Bortezomib could not alter transcriptional activities of beta-catenin dependent reporter and canonical Wnt signaling target gene expression. We also demonstrated that inhibition of certain ubiquitin ligase (E3) up-regulates the differentiation of osteoblasts.