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Aim: To test the hypothesis that genistein stimulates the osteoblastic differentia-tion through the p38 mitogen activated protein kinase (MAPK)-core-binding fac-tor 1 (Cbfal) pathway. Methods: The activation of p38 MAPK was detected byWeste blotting. Alkaline phosphatase (ALP) activity and calcium depositionwere assessed for osteoblastic differentiation of bone marrow-derived mesenchy-real stem cell (BMSC) cultures. The expression of Cbfal was analyzed at both the mRNA and protein levels. The activity of Cbfal was detected by electrophoreticmobility shift assay. Bone sialoprotein (BSP), ALP, osteocalcin (OC), and osteopontin (OPN) gene transcription were also evaluated by either RT-PCR or Northe blotting. Results: Genistein (0.01-1 μmol/L) dose dependently led to the rapid and sustained activation of the p38 MAPK pathway in mouse BMSC cultures. Treatment with genistein (1 μmol/L) resulted in increased ALP activity and calcium deposition of BMSC cultures as a function of time. Genistein also enhanced Cbfal DNA binding activity and promoted the expressions of Cbfa1 itself as well as several Cbfal-regulated genes, including ALP, BSP, OC, and OPN.Concurrent treatment with p38 MAPK inhibitor (SB203580) diminished the genistein-induced osteoblastic maturation and p38 MAPK-Cbfal activation in mouse BMSC cultures. Conclusion: These results indicated that genistein could stimulate the osteoblastic differentiation of BMSC cultures through the p38 MAPK-Cbfal pathway.