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Abstract
The osteogenic differentiation capacity of senescent bone marrow mesenchymal stem cells (MSCs) is reduced. p53 not only regulates cellular senescence but also functions as a negative regulator in bone formation. However, the role of p53 in MSCs senescence and differentiation has not been extensively explored. In the present study, we investigated the molecular mechanism of p53 in MSCs senescence and osteogenic differentiation. We found that p53 was upregulated during cellular senescence and osteogenic differentiation of MSCs respectively induced by H2O2 and BMP9. Similarly, the expression of p53-induced miR-145a was increased significantly. Furthermore, Overexpression of miR-145a in MSCs promoted cellular senescence and inhibited osteogenic differentiation. Then, we identified that p53-induced miR-145a inhibited osteogenic differentiation by targeting core binding factor beta (Cbfb), and the restoration of Cbfb expression rescued the inhibitory effects of miRNA-145a. In summary, our results indicate that p53/miR-145a axis exert its functions both in promoting senescence and inhibiting osteogenesis of MSCs, and the novel p53/miR-145a/Cbfb axis in osteogenic differentiation of MSCs may represent new targets in the treatment of osteoporosis.
Highlights
Primary osteoporosis is a disease closely related to ageing
Of all the predicted target genes, we found that Smad3, core binding factor beta (Cbfb), Smad5, Ctnnbip1, which was highlighted with blue colour in Figure 6A, are involved in osteogenic differentiation
The accumulation of aged mesenchymal stem cells (MSCs) in bone marrow tissue leads to the decreased ability of BMSCs to undergo osteogenic differentiation [3]
Summary
Primary osteoporosis is a disease closely related to ageing. The population ageing trend has led to an increasing number of osteoporosis patients worldwide [1]. The body is composed of numerous cells, and the ageing of the body is first manifested in the ageing of cells. Cell ageing in vitro may in a sense reflect the process of body ageing. Cellular senescence and ageing are not synonymous, senescence restricts the replicative life of a cell and has previously been validated as a primary mediator of aging [2]. The fundamental cause of osteoporosis is the imbalance between bone formation and bone resorption, and bone formation is mainly mediated by bone marrow
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