Metformin promotes the proliferation and differentiation of murine preosteoblast by regulating the expression ofsirt6andoct4

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Graphical abstractOsteopenia, osteoporosis and bone salt metabolism disorder are common diseases in the aged and diabetics. From case reports of patients with T2DM, we have observed that metformin can decrease risk of bone fracture and promote bone formation. However, the underlying mechanism of metformin's effect on bone metabolism remains unknown. In our research, we show that metformin can promote proliferation of murine preosteoblast by regulating AMPK-mTORC2 and AKT-mTORC1 signaling axis. Furthermore, we have observed that metformin can promote SIRT6 expression before and during differentiation of murine preosteoblast. The interaction between SIRT6 and NF-κB is highly important in osteoblast differentiation just as the relationship between OPG and RANKL in the process of bone formation. During differentiation, we show that SIRT6 inhibits phosphorylation of NF-κB and that OPG increases while RANKL decrease in HG groups. In addition, ablation of sirt6 in mice causes phosphorylation of NF-κB at high-levels and RANKL increases slightly in femur bone cells. However, other bone formation marker proteins such as RUNX2, OSTERIX and OPG appear at low-levels in sirt6 KO mice. It has been confirmed that downregulation of OCT4 is critical incident in the differentiation of embryonic stem cells. Fortunately, we observe that SIRT6 can suppress OCT4 expression in murine preosteoblast and the expression of OCT4 is at high-level in sirt6 KO mice. Taken together, this study's results illuminate metformin's effect on bone metabolism under HG condition and help to elucidate why metformin can promote bone fracture healing of patients with T2DM.

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