Bre Enhances Osteoblastic Differentiation By Promoting The Degradation Of P53

Background: Bre is a conserved cellular protein expressed in various tissues. Its major function includes DNA damage repair and anti-apoptosis. Recent studies indicate that Bre is potentially involved in stem cell differentiation although pathophysiological significance along with the molecular mechanisms are still unclear. Numerous studies also indicated that p53 plays significant functions in the osteogenesis processes. However, the signaling that regulates p53 in osteoblast differentiation remain poorly understood.Results: We find that Bre protein was substantially expressed in the bone tissue and its expression was highly upregulated during the osteogenic differentiation. Knockdown or overexpression Bre gene, as well as the in vivo bone formation experiments collectively indicated that Bre could promot the osteogenesis both in vitro and in vivo. We founded that knockdown of Bre led to upregulation of p53 expression and thus led to the osteogeneisis obstacles. However, when we inhibited the p53 by siRNA silencing or inhibitors, the impaired osteogenesis caused by Bre knockdown was greatly restored. Finally, we found that Bre promoted the Mdm2-mediated p53 ubiquitination and degradation by physically interacting with p53. Through analysis the promoter sequences of Bre gene, we find that Nur77 could initiate the transcription of Bre gene, and this results were certificated by dual luciferase report systems. The Bre gene knockout mouse was also generated and through microCT analysis we find that knockout Bre gene didn’t significantly influence the early bone development of the mouse. However, the functions of Bre on the old mouse bone metabolisms need further experiments analysis.Conclusions: In conclusions, the results from the current study demonstrate that Bre is a positive regulator of osteoblastic differentiation, both in vitro and in vivo. We report for the first time that Bre interacts with p53 and participates in osteoblastic differentiation via promoting Mdm2-mediated p53 protein ubiquitination and degradation. These results shed important insight on understanding of the regulatory mechanisms for Bre and p53 in osteogenesis. Our study also suggests that targeting Bre or p53 related pathways could become a potential therapeutic strategy for the treatment of metabolic bone diseases.