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The protein levels of Runx2, Col1a1 and osteocalcin(OCN) were also increased by fisetin. Furthermore, fisetin activated the phosphoinositide-3-kinase/protein kinase B (PI3K-AKT) signaling pathway, and blocking this pathway by the inhibitor LY-294002 could impair fisetin's functions on proliferation, differentiation and OPG/RANKL expression ratio in the MC3T3-E1 cells. Our results demonstrated that fisetin could promote MC3T3-E1 cell proliferation, differentiation, and increase OPG/RANKL expression ratio through activating the PI3K-AKT pa