Effects of high-fat diet on gene expression and chromatin accessibility of bone marrow mesenchymal stem cells (BMSCs) (PRJCA018789)

Consumption of a high-fat diet (HFD) has been linked to reduced bone formation, a key contributor to HFD-induced osteoporosis and increased risk of fragility fractures. Our research has demonstrated that this event may be caused by premature senescence of bone marrow mesenchymal stem cells (BMSCs), which exhibit reduced proliferative and osteogenic capacities after HFD exposure. To further investigate the underlying driving factor of BMSC senescence, we examined the transcriptional program and chromatin accessibility landscape within BMSCs after HFD consumption. Our findings suggest that there is a global decrease in chromatin accessibility of VDR binding sequences and VDR signaling in HFD BMSCs, indicating VDR as a key regulator during BMSC senescence. Activation of VDR protected BMSCs from senescence caused by a main component of HFD (palmitic acid), enhanced their proliferative and osteogenic abilities. VDR activator administration in mice also rescued BMSC senescence and significantly improved osteogenesis, bone mass and other bone parameters in HFD mice. In addition, we revealed that the downregulation of VDR led to the accumulation of intracellular ROS levels due to the inhibited expression of VDR downstream molecule SOD2, which drove BMSC senescence. Collectively, these results demonstrate that a reduction of VDR after HFD exposure leads to BMSC senescence and associated osteoporosis, which may be mediated through alterations in the SOD2-ROS axis. Our findings provide novel insights into the treatment of osteoporosis induced by HFD through transcription-factor-binding events of VDR.