Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Oral and Maxillofacial Surgery, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.
Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; Global Medical Science Education Unit, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Biochem Pharmacol. 2014 Aug 15;90(4):397-405. doi: 10.1016/j.bcp.2014.06.011. Epub 2014 Jun 20.
Inhibition of glycogen synthase kinase (GSK)-3 and the consequent activation of the Wnt/β-catenin signaling pathway have been reported to increase bone volume. To develop a novel pharmacotherapy for injured bone, we investigated whether GSK-3 inhibitor was effective in promoting bone formation. In in vitro experiments, we examined the effects of GSK-3 inhibitors LiCl and SB216763 on osteoblastogenesis of mesenchymal progenitor C3H10T1/2 cells and osteoclastogenesis of osteoclast precursor RAW-D cells. Both inhibitors promoted osteoblast differentiation, assessed by alkaline phosphatase activity and calcium deposition, stimulating the Wnt/β-catenin signaling pathway and thereby inducing Runx2. On the other hand, the GSK-3 inhibitors suppressed osteoclast differentiation, assessed by tartrate-resistant acid phosphatase staining and number of nuclei in the cells, reducing NFATc1 expression independently of the Wnt/β-catenin signaling pathway. In subsequently performed in vivo studies, we examined the effect of locally administered Li2CO3 on the recovery from a partial defect made on the rat tibia. Computerized tomography and bone histomorphometry showed that Li2CO3 accelerated bone regeneration in defect lesion with increased lamellar bone ratio compared with the controls. These results suggested that local application of lithium (or other GSK-3 inhibitors) might effectively facilitate recovery from bone injury by promoting osteoblastogenesis and inhibiting osteoclastogenesis.
抑制糖原合酶激酶（GSK）-3 并激活 Wnt/β-连环蛋白信号通路已被报道可增加骨量。为了开发治疗受损骨骼的新药物疗法，我们研究了 GSK-3 抑制剂是否能有效促进骨形成。在体外实验中，我们研究了 GSK-3 抑制剂 LiCl 和 SB216763 对间充质祖细胞 C3H10T1/2 细胞成骨分化和破骨细胞前体 RAW-D 细胞破骨分化的影响。两种抑制剂均通过刺激 Wnt/β-连环蛋白信号通路并诱导 Runx2 来促进碱性磷酸酶活性和钙沉积评估的成骨分化。另一方面，GSK-3 抑制剂通过抗酒石酸酸性磷酸酶染色和细胞核数量来抑制破骨分化，独立于 Wnt/β-连环蛋白信号通路减少 NFATc1 表达。在随后进行的体内研究中，我们研究了局部给予 Li2CO3 对大鼠胫骨部分缺损恢复的影响。计算机断层扫描和骨组织形态计量学显示，与对照组相比，Li2CO3 加速了缺损病变中的骨再生，增加了板层骨比例。这些结果表明，通过促进成骨和抑制破骨，局部应用锂（或其他 GSK-3 抑制剂）可能有效促进骨损伤的恢复。
