Glycogen Synthase Kinase-3α/β Inhibition Promotes In Vivo Amplification of Endogenous Mesenchymal Progenitors With Osteogenic and Adipogenic Potential and Their Differentiation to the Osteogenic Lineage
Glycogen Synthase Kinase-3α/β Inhibition Promotes In Vivo Amplification of Endogenous Mesenchymal Progenitors With Osteogenic and Adipogenic Potential and Their Differentiation to the Osteogenic Lineage
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DOI：
10.1002/jbmr.266
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发表时间：
2011-04-01
影响因子：
6.2
通讯作者：
Bellantuono, Ilaria
中科院分区：
文献类型：
--
作者：
Gambardella, Alessandra;Nagaraju, Chandan K.;Bellantuono, Ilaria
小分子是扩增和指导干细胞分化的有吸引力的治疗剂。它们也可以用来理解通过干扰特定的信号通路来调节它们的命运。间充质干细胞（MSC）具有增殖和分化成多种细胞类型的潜力，包括成骨细胞。通过抑制糖原合成酶激酶3（GSK-3）激活经典Wnt信号传导已被证明可增强骨量，这可能涉及从间充质干细胞库的扩增到成骨细胞的定型和分化的许多机制。在这里，我们使用了一种高度特异性的新型GSK-3抑制剂AR 28，能够诱导β-连环蛋白核转位，并在BALB/c小鼠中治疗14天后增加骨量。我们已经显示了一个时间调节的数量增加的集落形成单位成骨细胞（CFU-O）和脂肪细胞（CFU-A），但不是集落形成单位成纤维细胞（CFU-F）在小鼠治疗3天。治疗14 d后，CFU-O、CFU-A数量恢复正常，CFU-F数量明显减少。相比之下，成骨细胞的数量仅在治疗14天后才显著增加，并且这与骨髓肥胖的显著减少一起被观察到。这些数据表明，骨量增加是具有成骨和成脂潜能的MSC亚群扩增的早期时间波的结果，其以脂肪生成为代价被驱动成骨细胞分化。(C)2011年美国骨与矿物质研究学会。
Small molecules are attractive therapeutics to amplify and direct differentiation of stem cells. They also can be used to understand the regulation of their fate by interfering with specific signaling pathways. Mesenchymal stem cells (MSCs) have the potential to proliferate and differentiate into several cell types, including osteoblasts. Activation of canonical Wnt signaling by inhibition of glycogen synthase kinase 3 (GSK-3) has been shown to enhance bone mass, possibly by involving a number of mechanisms ranging from amplification of the mesenchymal stem cell pool to the commitment and differentiation of osteoblasts. Here we have used a highly specific novel inhibitor of GSK-3, AR28, capable of inducing beta-catenin nuclear translocation and enhanced bone mass after 14 days of treatment in BALB/c mice. We have shown a temporally regulated increase in the number of colony-forming units-osteoblast (CFU-O) and -adipocyte (CFU-A) but not colony-forming units-fibroblast (CFU-F) in mice treated for 3 days. However, the number of CFU-O and CFU-A returned to normal levels after 14 days of treatment, and the number of CFU-F was decreased significantly. In contrast, the number of osteoblasts increased significantly only after 14 days of treatment, and this was seen together with a significant decrease in bone marrow adiposity. These data suggest that the increased bone mass is the result of an early temporal wave of amplification of a subpopulation of MSCs with both osteogenic and adipogenic potential, which is driven to osteoblast differentiation at the expense of adipogenesis. (C) 2011 American Society for Bone and Mineral Research.