Investigation for GSK3β expression in diabetic osteoporosis and negative osteogenic effects of GSK3β on bone marrow mesenchymal stem cells under a high glucose microenvironment

Osteoporosis is a common skeletal complication of diabetes mellitus (DM). The mechanisms underlying the pathophysiology of diabetic osteoporosis are complex. Glycogen synthase kinase-3β (GSK-3β) is a widely expressed serine/threonine kinase and associated with both DM and bone metabolism, which arouse our concern. In this study, we established the diabetic mouse model by high-fat diet combined with streptozotocin injection. Decreased bone mass and reduced osteogenesis were observed in femurs of the mice. Besides, we identified that there is an activated expression of GSK3β in the bone marrow mesenchymal stem cells (BMSCs) of diabetic mice. To explore the link between GSK3β and diabetic osteoporosis, we exposed BMSCs to a high glucose microenvironment in vitro and discovered that the glucose-induced GSK3β activation has negative osteogenic effects on BMSCs by suppressing β-catenin/Tcf7/Ccn4 signaling axis. Inhibition of GSK3β by specific concentrations of LiCl could reverse the impaired osteogenesis of BMSCs and increase expression of β-catenin, Tcf7 and Ccn4. Our research indicated that abnormal activation of GSK3β plays a role in diabetic osteoporosis and might be a potential target to treat diabetic osteoporosis. •Decreased bone mass and reduced osteogenesis in HFD + STZ mice is associated with GSK3β activation.•GSK3β activation leads to the adverse osteogenesis of BMSCs under a high glucose microenvironment.•Glucose-induced GSK3β activation suppresses β-catenin/Tcf7/Ccn4 signaling axis.