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Browsing by Author "Tanjung, Nancy"
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Item Predicting and validating the pathway of Wnt3a-driven suppression of osteoclastogenesis(Elsevier, 2014-11) Hamamura, Kazunori; Chen, Andy; Nishimura, Akinobu; Tanjung, Nancy; Sudo, Akihiro; Yokota, Hiroki; Department of Anatomy & Cell Biology, IU School of MedicineWnt 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.Item Suppression of Osteoclastogenesis via Upregulation of Zfyve21 and Ddit4 by Salubrinal and Guanabenz(2016) Hamamura, Kazunori; Tanjung, Nancy; Chen, Andy; Yokota, Hiroki; Togari, Akifumi; Department of Biomedical Engineering, School of Engineering and TechnologySalubrinal and guanabenz are two known inhibitors of de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α), and they suppress osteoclastogenesis through downregulating nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a master molecule of osteoclastogenesis. The mechanism of NFATc1 suppression is not well understood. Using genome-wide microarray analysis, we investigated molecular regulators of osteoclastogenesis, in particular, in response to salubrinal and guanabenz. We identified two sets of genes: a set of genes that were upregulated by receptor activator of nuclear factor kappa-B ligand (RANKL) and downregulated by salubrinal and guanabenz; and the other set of genes that were downregulated by RANKL and upregulated by salubrinal and guanabenz. The microarray and qPCR result revealed that a zinc finger protein, FYVE domain containing 21 (Zfyve21), as well as DNA-damage-inducible transcript 4 (Ddit4), were suppressed by RANKL and upregulated by salubrinal and guanabenz. A partial silencing of Zfyve21 or Ddit4 attenuated salubrinal- and guanabenz-driven suppression of NFATc1. Collectively, this study demonstrates that Zfyve21 and Ddit4 are two inhibitors of osteoclastogenesis. We expect that they may potentially serve as novel targets for preventing bone loss from skeletal diseases such as osteoporosis.