Predicting and validating the pathway of Wnt3a-driven suppression of osteoclastogenesis.
Predicting and validating the pathway of Wnt3a-driven suppression of osteoclastogenesis.
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DOI：
10.1016/j.cellsig.2014.07.018
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发表时间：
2014-11
影响因子：
4.8
通讯作者：
Yokota H
中科院分区：
文献类型：
--
作者：
Hamamura K;Chen A;Nishimura A;Tanjung N;Sudo A;Yokota H
Wnt信号在骨稳态和机械转导中发挥重要作用，但其在破骨细胞发育中的作用和调控机制尚不完全清楚。通过全基因组的芯片分析，我们研究了wnt3a驱动的破骨细胞发育调控。在Wnt3a存在和不存在的情况下，用RANKL培养小鼠骨髓源性细胞。利用微阵列mRNA表达数据，我们进行了主成分分析，并预测了可能参与RANKL和Wnt3a应答的转录因子结合位点（TFBSs）。主成分分析预测了潜在的Wnt3a响应性调节因子将逆转破骨细胞的发育，而TFBS预测算法表明AP1结合位点将与Wnt3a驱动的抑制有关。由于c-Fos被RANKL上调，而被Wnt3a下调，并呈剂量依赖性，我们使用RNA干扰来研究其作用。c-Fos的部分沉默通过下调NFATc1（破骨细胞发育的主要转录因子）来抑制rankl驱动的破骨细胞生成。虽然可以预测c-Myc的参与，并且部分沉默c-Myc会略微降低TRAP的水平，但c-Myc沉默并没有改变NFATc1的表达。总的来说，本文提出的系统生物学方法表明，Wnt3a通过阻断c-Fos表达来减弱rankl驱动的破骨细胞的发生，并表明骨的机械转导不仅通过Wnt信号改变成骨细胞的发育，也通过Wnt信号改变破骨细胞的发育。
Wnt signaling plays a major role in bone homeostasis and mechanotransduction, but its role and regulatory mechanism in osteoclast development are not fully understood. Through genome-wide in silico analysis, we examined Wnt3a-driven regulation of osteoclast development. Mouse bone marrow-derived cells were incubated with RANKL in the presence and absence of Wnt3a. Using microarray mRNA expression data, we conducted principal component analysis and predicted transcription factor binding sites (TFBSs) that were potentially involved in the responses to RANKL and Wnt3a. The principal component analysis predicted potential Wnt3a responsive regulators that would reverse osteoclast development, and a TFBS prediction algorithm indicated that the AP1 binding site would be linked to Wnt3a-driven suppression. Since c-Fos was upregulated by RANKL and downregulated by Wnt3a in a dose-dependent manner, we examined its role using RNA interference. The partial silencing of c-Fos suppressed RANKL-driven osteoclastogenesis by downregulating NFATc1, a master transcription factor of osteoclast development. Although the involvement of c-Myc was predicted and partially silencing c-Myc slightly reduced the level of TRAP, c-Myc silencing did not alter the expression of NFATc1. Collectively, the presented systems-biology approach demonstrates that Wnt3a attenuates RANKL-driven osteoclastogenesis by blocking c-Fos expression and suggests that mechanotransduction of bone alters the development of not only osteoblasts but also osteoclasts through Wnt signaling.
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DOI：
10.1083/jcb.201207142
发表时间：
2013-02-18
期刊：
The Journal of cell biology
影响因子：
--
作者：
Albers J;Keller J;Baranowsky A;Beil FT;Catala-Lehnen P;Schulze J;Amling M;Schinke T
通讯作者：
Schinke T
影响因子：
4.8
作者：
Nakashima, A;Katagiri, T;Tamura, M
通讯作者：
Tamura, M
DOI：
10.1152/ajplung.00140.2010
发表时间：
2010-11-01
影响因子：
4.9
作者：
Liu, Xiaoming;Luo, Meihui;Engelhardt, John F.
通讯作者：
Engelhardt, John F.
影响因子：
3.4
作者：
Tamura, Masato;Uyama, Maki;Sato, Mari
通讯作者：
Sato, Mari
影响因子：
11.8
作者：
Day, TF;Guo, XZ;Yang, YZ
通讯作者：
Yang, YZ