Abstract
ABSTRACTThe bone marrow mesenchymal stem cells (BMSCs)-mediated abnormal bone metabolism can delay and impair the bone remodeling process in type 2 diabetes mellitus (T2DM). Our previous study demonstrated that the downregulation of brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1), a circadian clock protein, inhibited the Wnt/β-catenin pathway via enhanced GSK-3β in diabetic BMSCs. In this article, we confirmed that the downregulated BMAL1 in T2DM played an inhibitory role in osteogenic differentiation of BMSCs. Upregulation of BMAL1 in the diabetic BMSCs significantly recovered the expression pattern of osteogenic marker genes and alkaline phosphatase (Alp) activity. We also observed an activation of the p53 signaling pathways, exhibited by increased p53 and p21 in diabetic BMSCs. Downregulation of p53 resulting from overexpression of BMAL1 was detected, and when we applied p53 gene silencing (shRNA) and the p53 inhibitor, pifithrin-α (PFT-α), the impaired osteogenic differentiation ability of diabetic BMSCs was greatly restored. However, there was no change in the level of expression of BMAL1. Taken together, our results first revealed that BMAL1 regulated osteogenesis of BMSCs through p53 in T2DM, providing a novel direction for further exploration of the mechanism underlying osteoporosis in diabetes.
Highlights
As a chronic metabolic disorder disease, diabetes mellitus (DM) has affected millions of people, and its prevalence has been increasing significantly worldwide (Guariguata et al, 2014)
Characteristics of Bone marrow mesenchymal stem cells (BMSCs) Flow cytometric analysis of phenotypic expression showed that CD34 and CD45 were negatively expressed, while CD29, CD44 and CD90 were positively expressed in cells from both groups (Fig. 1A)
Overexpression of BMAL1 rescued the impaired osteogenic differentiation of BMSCs in type 2 diabetes mellitus (T2DM) Our previous research has demonstrated that expression of BMAL1 was clearly downregulated in diabetic BMSCs (Li et al, 2017)
Summary
As a chronic metabolic disorder disease, diabetes mellitus (DM) has affected millions of people, and its prevalence has been increasing significantly worldwide (Guariguata et al, 2014). More than 90% of these patients are diagnosed with type 2 diabetes mellitus (T2DM) (McGurnaghan et al, 2019). Most of them are suffering from osteoporosis and following fractures. Bone marrow mesenchymal stem cells (BMSCs) are vital for bone regeneration, due to its multidirectional differentiation potential and the differentiation ability. Previous studies revealed that the proliferation and multipotency of BMSCs might change in diabetic pathological microenvironment (Zhou et al, 2016). BMSCs-mediated imbalance of bone formation and bone resorption would occur in T2DM (Brown et al, 2014). There have been few articles on the molecular mechanisms of diabetic osteoporosis until now
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