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　is　still　unclear.　Here,　we　report　that　Bre　protein　was　substantially　expressed　in　the　bone　tissue　and　its　expression　was　highly　upregulated　during　the　osteogenic　differentiation.　To　test　a　hypothesis　that　Bre　plays　functional　roles　in　the　process　of　osteogenic　differentiation,　we　examined　the　expression　of　Bre　in　an　osteoporosis　mouse　model.　Compared　with　the　normal　bone　tissue,　Bre　expression　in　osteoporotic　bone　was　also　significantly　reduced.　Moreover,　knockdown　of　Bre　in　the　mouse　bone　marrow　mesenchymal　cells　significantly　reduced　the　expression　of　osteogenic　marker　genes,　the　alkaline　phosphatase　activity,　and　the　mineralization　capacity,　while　overexpression　of　Bre　greatly　promoted　the　osteogenesis　both　in　vitro　and　in　vivo.　Interestingly,　we　founded　that　knockdown　of　Bre　led　to　activation　of　the　p53　signaling　pathways　exhibited　by　increased　p53,　p21,　and　Mdm2.　However,　when　we　inhibited　the　p53　by　siRNA　silencing　or　pifithrin-z　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.　Taken　together,　our　results　revealed　a　novel　function　of　Bre　in　osteoblast　differentiation　through　modulating　the　stability　of　p53.