The inhibitors of cyclin-dependent kinases and GSK-3β enhance osteoclastogenesis.
The inhibitors of cyclin-dependent kinases and GSK-3β enhance osteoclastogenesis.
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DOI：
10.1016/j.bbrep.2015.12.011
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发表时间：
2016-03
影响因子：
2.7
通讯作者：
Saeki M
中科院分区：
文献类型：
--
作者：
Akiba Y;Mizuta A;Kakihara Y;Nakata J;Nihara J;Saito I;Egusa H;Saeki M
破骨细胞是多核细胞，具有骨吸收活性，对骨重建至关重要。RANK-RANKL(核因子受体激活剂κB配体)信号通路是破骨细胞分化的主要信号通路。然而，其分子机制和调控破骨细胞形成的因素仍不完全清楚。在这项研究中，我们进行了化学遗传筛选，并确定了CDKs/GSK-3β(细胞周期蛋白依赖蛋白依赖的激酶/糖原合成酶激酶3β)抑制剂kenpaulone，以及两种CDKs抑制剂olomouine和rocovitine，它们都通过上调活化T细胞核因子1(NFATc1)的水平显著促进RAW264.7细胞的破骨细胞生成。我们还确定，这三种化合物都能增加小鼠骨髓细胞分化为破骨细胞的数量。此外，这三种抑制剂，特别是凯普隆，促进了组织蛋白酶K的成熟，表明由此产生的破骨细胞的吸收活性也被激活。我们的研究结果表明，抑制GSK-3RANKL和/或CDK通过调节RANK-β信号通路促进破骨细胞的形成。我们进行了化学基因筛查，以确定调节破骨细胞生成的药物。筛选确定CDK/GSK-3β抑制剂肯保隆和两种CDK抑制剂奥洛莫辛和罗斯科维汀为破骨细胞生成的激活剂。Kenpaulone、olomouine和rocovitine通过上调NFATc1和成熟组织蛋白酶K的水平来诱导破骨细胞的形成。
Osteoclasts are multinucleated cells with bone resorption activity that is crucial for bone remodeling. RANK‐RANKL (receptor activator of nuclear factor κB ligand) signaling has been shown as a main signal pathway for osteoclast differentiation. However, the molecular mechanism and the factors regulating osteoclastogenesis remain to be fully understood. In this study, we performed a chemical genetic screen, and identified a Cdks/GSK-3β (cyclin-dependent kinases/glycogen synthase kinase 3β) inhibitor, kenpaullone, and two Cdks inhibitors, olomoucine and roscovitine, all of which significantly enhance osteoclastogenesis of RAW264.7 cells by upregulating NFATc1 (nuclear factor of activated T cells, cytoplasmic 1) levels. We also determined that the all three compounds increase the number of osteoclast differentiated from murine bone marrow cells. Furthermore, the three inhibitors, especially kenpaullone, promoted maturation of cathepsin K, suggesting that the resorption activity of the resultant osteoclasts is also activated. Our findings indicate that inhibition of GSK-3β and/or Cdks enhance osteoclastogenesis by modulating the RANK–RANKL signaling pathway. We performed a chemical genetic screen to identify drugs which modulate osteoclastogenesis. The screening determined a Cdk/GSK-3β inhibitor, kenpaullone, and two Cdk inhibitors, olomoucine and roscovitine, as activators of osteoclastogenesis. The kenpaullone, olomoucine, and roscovitine induce an enhanced osteoclastogenesis by upregulating NFATc1 and mature cathepsin K levels.