Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, China.
Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, China.
Biochem Biophys Res Commun. 2021 Jan 1;534:727-733. doi: 10.1016/j.bbrc.2020.11.010. Epub 2020 Nov 13.
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.
骨质疏松症是糖尿病（DM）常见的骨骼并发症。糖尿病性骨质疏松症的病理生理学机制复杂。糖原合成酶激酶-3β（GSK-3β）是一种广泛表达的丝氨酸/苏氨酸激酶，与 DM 和骨代谢都有关联，这引起了我们的关注。在这项研究中，我们通过高脂肪饮食联合链脲佐菌素注射建立了糖尿病小鼠模型。在这些小鼠的股骨中，观察到骨量减少和成骨减少。此外，我们发现糖尿病小鼠骨髓间充质干细胞（BMSCs）中存在 GSK3β 的激活表达。为了探究 GSK3β 与糖尿病性骨质疏松症之间的联系，我们在体外将 BMSCs 暴露于高葡萄糖微环境中，发现葡萄糖诱导的 GSK3β 激活通过抑制 β-连环蛋白/Tcf7/Ccn4 信号轴对 BMSCs 产生负性成骨作用。特定浓度的 LiCl 抑制 GSK3β 可逆转 BMSCs 的受损成骨，并增加 β-连环蛋白、Tcf7 和 Ccn4 的表达。我们的研究表明，GSK3β 的异常激活在糖尿病性骨质疏松症中起作用，可能是治疗糖尿病性骨质疏松症的潜在靶点。
