Abstract
BackgroundProgressive population aging has contributed to the increased global prevalence of diabetes and osteoporosis. Inhibition of osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) by hyperglycemia is a potential pathogenetic mechanism of osteoporosis in diabetic patients. Uncarboxylated osteocalcin (GluOC), a protein secreted by mature osteoblasts, regulates bone development as well as glucose and lipid metabolism. In our previous studies, GluOC was shown to promote osteoblastic differentiation of BMSCs; however, the underlying mechanisms are not well characterized. Tumor protein 63 (TP63), as a transcription factor, is closely related to bone development and glucose metabolism.ResultsIn this study, we verified that high glucose suppressed osteogenesis and upregulated adipogenesis in BMSCs, while GluOC alleviated this phenomenon. In addition, high glucose enhanced TP63 expression while GluOC diminished it. Knock-down of TP63 by siRNA transfection restored the inhibitory effect of high glucose on osteogenic differentiation. Furthermore, we detected the downstream signaling pathway PTEN/Akt/GSK3β. We found that diminishing TP63 decreased PTEN expression and promoted the phosphorylation of Akt and GSK3β. We then applied the activator and inhibitor of Akt, and concluded that PTEN/Akt/GSK3β participated in regulating the differentiation of BMSCs.ConclusionsOur results indicate that GluOC reduces the inhibitory effect of high glucose on osteoblast differentiation by regulating the TP63/PTEN/Akt/GSK3β pathway. TP63 is a potential novel target for the prevention and treatment of diabetic osteoporosis.
Highlights
Progressive population aging has contributed to the increased global prevalence of diabetes and osteoporosis
These results indicated that GluOC alleviated high glucose-induced suppression of osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs)
PTEN/Akt/GSK3β participated in regulating the differentiation of BMSCs We probed the impact of the PTEN/Akt/GSK3β pathway on osteogenesis by using 740Y-P (25 μM) or LY294002 (10 μM). 740Y-P is the activator of Akt and LY294002 is the inhibitor of Akt
Summary
Progressive population aging has contributed to the increased global prevalence of diabetes and osteoporosis. Inhibition of osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) by hyperglycemia is a potential pathogenetic mechanism of osteoporosis in diabetic patients. Uncarboxylated osteocalcin (GluOC), a protein secreted by mature osteoblasts, regulates bone development as well as glucose and lipid metabolism. GluOC was shown to promote osteoblastic differentiation of BMSCs; the underlying mechanisms are not well characterized. Tumor protein 63 (TP63), as a transcription factor, is closely related to bone development and glucose metabolism. Osteoporosis is one of the several potential long-term complications of diabetes mellitus [2]. It is important to explore the potential mechanism of high glucose level inhibition on osteogenic differentiation of BMSCs and identify relevant targets for the treatment of diabetes-induced osteoporosis
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