Postnatal bone marrow contains mesenchymal stem cells (MSCs) that are osteoblast precursors with great therapeutic potential. The oxygen tension in bone marrow is about 1-7% pO2 which is much lower than that of the external environment. The effect of these hypoxic conditions on MSC differentiation is not fully understood. In this study, we show that hypoxia inhibits osteogenic differentiation of MSCs, and that this effect is associated with increased levels of Notch1 and increased activity of Notch signaling. Knockdown of Notch1 in MSCs by shRNA markedly rescues the impaired osteogenic differentiation of MSCs. Furthermore, Notch1 physiologically binds to Runx2 and inhibits its transcriptional activity. Thus, hypoxia inhibits MSC differentiation into osteoblasts by activating the Notch pathway.
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