Zahoor Muhammad, Cha Pu-Hyeon, Min Do Sik, Choi Kang-Yell
Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea; Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
J Bone Miner Res. 2014;29(5):1196-205. doi: 10.1002/jbmr.2147.
Osteoporosis is a major global health issue in elderly people. Because Wnt/β-catenin signaling plays a key role in bone homeostasis, we screened activators of this pathway through cell-based screening, and investigated indirubin-3'-oxime (I3O), one of the positive compounds known to inhibit GSK3β, as a potential anti-osteoporotic agent. Here, we show that I3O activated Wnt/β-catenin signaling via inhibition of the interaction of GSK3β with β-catenin, and induced osteoblast differentiation in vitro and increased calvarial bone thickness ex vivo. Intraperitoneal injection of I3O increased bone mass and improved microarchitecture in normal mice and reversed bone loss in an ovariectomized mouse model of age-related osteoporosis. I3O also increased thickness and area of cortical bone, indicating improved bone strength. Enhanced bone mass and strength correlated with activated Wnt/β-catenin signaling, as shown by histological analyses of both trabecular and cortical bones. I3O also restored mass and density of bone in hindlimb-unloaded mice compared with control, suspended mice, demonstrating bone-restoration effects of I3O in non-aged-related osteoporosis as well. Overall, I3O, a pharmacologically active small molecule, could be a potential therapeutic agent for the treatment and prevention of osteoporosis.
骨质疏松症是老年人面临的一个重大全球健康问题。由于Wnt/β-连环蛋白信号通路在骨稳态中起关键作用，我们通过基于细胞的筛选方法筛选了该信号通路的激活剂，并研究了靛玉红-3'-肟（I3O），它是已知的抑制糖原合成酶激酶3β（GSK3β）的阳性化合物之一，作为一种潜在的抗骨质疏松药物。在此，我们表明I3O通过抑制GSK3β与β-连环蛋白的相互作用来激活Wnt/β-连环蛋白信号通路，并在体外诱导成骨细胞分化，在体内增加颅骨厚度。腹腔注射I3O可增加正常小鼠的骨量并改善骨微结构，还能逆转去卵巢老龄骨质疏松小鼠模型中的骨质流失。I3O还增加了皮质骨的厚度和面积，表明骨强度得到改善。骨量和强度的增加与激活的Wnt/β-连环蛋白信号通路相关，这在小梁骨和皮质骨的组织学分析中均有体现。与对照悬吊小鼠相比，I3O还恢复了后肢失用小鼠的骨量和骨密度，这表明I3O在非老龄相关骨质疏松症中也具有骨修复作用。总体而言，I3O作为一种具有药理活性的小分子，可能是治疗和预防骨质疏松症的潜在治疗药物。
