Suppression of osteoclastogenesis via upregulation of Zfyve21 and Ddit4 by salubrinal and guanabenz

KAZUNORI HAMAMURA, NANCY TANJUNG, ANDY CHEN, HIROKI YOKOTA, AKIFUMI TOGARI
2016 ORAL THERAPEUTICS AND PHARMACOLOGY  
Salubrinal and guanabenz are two known inhibitors of dephosphorylation 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
more » ... anabenz. 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.
doi:10.11263/jsotp.16.16 fatcat:qxdudfhdorfutiz4ug5nm43iiu