Osteoporosis is a common skeletal complication of diabetes mellitus (DM). The mechanisms underlying the pathophysiology of diabetic osteoporosis are complex. Glycogen synthase kinase-3 beta (GSK-3 beta) 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 GSK3 beta in the bone marrow mesenchymal stem cells (BMSCs) of diabetic mice. To explore the link between GSK3 beta and diabetic osteoporosis, we exposed BMSCs to a high glucose microenvironment in vitro and discovered that the glucose-induced GSK3 beta activation has negative osteogenic effects on BMSCs by suppressing beta-catenin/Tcf7/Ccn4 signaling axis. Inhibition of GSK3 beta by specific concentrations of LiCl could reverse the impaired osteogenesis of BMSCs and increase expression of beta-catenin, Tcf7 and Ccn4. Our research indicated that abnormal activation of GSK3 beta plays a role in diabetic osteoporosis and might be a potential target to treat diabetic osteoporosis. (C) 2020 Elsevier Inc. All rights reserved.