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NRROS Negatively Regulates Osteoclast Differentiation by Inhibiting RANKL-Mediated NF-κB and Reactive Oxygen Species Pathways

  • Kim, Jung Ha (Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School) ;
  • Kim, Kabsun (Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School) ;
  • Kim, Inyoung (Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School) ;
  • Seong, Semun (Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School) ;
  • Kim, Nacksung (Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School)
  • Received : 2015.06.19
  • Accepted : 2015.08.13
  • Published : 2015.10.31

Abstract

Negative regulator of reactive oxygen species (NRROS) is known to repress ROS generation in phagocytes. In this study, we examined the roles of NRROS in both osteoclasts and osteoblasts. Our results demonstrate that NRROS negatively regulates the differentiation of osteoclasts, but not osteoblasts. Further, overexpression of NRROS in osteoclast precursor cells attenuates RANKL-induced osteoclast differentiation. Conversely, osteoclast differentiation is enhanced upon siRNA-mediated knock-down of NRROS. Additionally, NRROS attenuates RANKL-induced $NF-{\kappa}B$ activation, as well as degradation of the NOX1 and NOX2 proteins, which are required for ROS generation. Based on our observations, we present NRROS as a novel negative regulator of RANKL-induced osteoclastogenesis.

Keywords

References

  1. Boyle, W.J., Simonet, W.S., and Lacey, D.L. (2003). Osteoclast differentiation and activation. Nature 423, 337-342. https://doi.org/10.1038/nature01658
  2. Grigoriadis, A.E., Wang, Z.Q., Cecchini, M.G., Hofstetter, W., Felix, R., Fleisch, H.A., and Wagner, E.F. (1994). c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science (New York, N.Y.) 266, 443-448. https://doi.org/10.1126/science.7939685
  3. He, Y., Staser, K., Rhodes, S.D., Liu, Y., Wu, X., Park, S.J., Yuan, J., Yang, X., Li, X., Jiang, L., et al. (2011). Erk1 positively regulates osteoclast differentiation and bone resorptive activity. PloS one 6, e24780. https://doi.org/10.1371/journal.pone.0024780
  4. Johnson, R.S., Spiegelman, B.M., and Papaioannou, V. (1992). Pleiotropic effects of a null mutation in the c-fos proto-oncogene. Cell 71, 577-586. https://doi.org/10.1016/0092-8674(92)90592-Z
  5. Kamiya, N. (2012). The role of BMPs in bone anabolism and their potential targets SOST and DKK1. Curr. Mol. Pharmacol. 5, 153-163. https://doi.org/10.2174/1874467211205020153
  6. Kim, J.H., and Kim, N. (2014). Regulation of NFATc1 in Osteoclast Differentiation. J. Bone Metabol. 21, 233-241. https://doi.org/10.11005/jbm.2014.21.4.233
  7. Kim, K., Kim, J.H., Lee, J., Jin, H.M., Lee, S.H., Fisher, D.E., Kook, H., Kim, K.K., Choi, Y., and Kim, N. (2005). Nuclear factor of activated T cells c1 induces osteoclast-associated receptor gene expression during tumor necrosis factor-related activationinduced cytokine-mediated osteoclastogenesis. J. Biol. Chem. 280, 35209-35216. https://doi.org/10.1074/jbc.M505815200
  8. Kim, K., Kim, J.H., Lee, J., Jin, H.M., Kook, H., Kim, K.K., Lee, S.Y., and Kim, N. (2007). MafB negatively regulates RANKLmediated osteoclast differentiation. Blood 109, 3253-3259. https://doi.org/10.1182/blood-2006-09-048249
  9. Kim, K., Lee, S.H., Ha Kim, J., Choi, Y., and Kim, N. (2008). NFATc1 induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP). Mol. Endocrinol. 22, 176-185. https://doi.org/10.1210/me.2007-0237
  10. Kim, K., Kim, J.H., Kim, I., Lee, J., Seong, S., Park, Y.W., and Kim, N. (2015). MicroRNA-26a regulates RANKL-induced osteoclast formation. Mol. Cells 38, 75-80.
  11. Lambeth, J.D. (2004). NOX enzymes and the biology of reactive oxygen. Nat. Rev. Immunol. 4, 181-189. https://doi.org/10.1038/nri1312
  12. Lee, N.K., Choi, Y.G., Baik, J.Y., Han, S.Y., Jeong, D.W., Bae, Y.S., Kim, N., and Lee, S.Y. (2005). A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation. Blood 106, 852-859. https://doi.org/10.1182/blood-2004-09-3662
  13. Moon, J.B., Kim, J.H., Kim, K., Youn, B.U., Ko, A., Lee, S.Y., and Kim, N. (2012). Akt induces osteoclast differentiation through regulating the GSK3beta/NFATc1 signaling cascade. J. Immunol. 188, 163-169. https://doi.org/10.4049/jimmunol.1101254
  14. Noubade, R., Wong, K., Ota, N., Rutz, S., Eidenschenk, C., Valdez, P.A., Ding, J., Peng, I., Sebrell, A., Caplazi, P., et al. (2014). NRROS negatively regulates reactive oxygen species during host defence and autoimmunity. Nature 509, 235-239. https://doi.org/10.1038/nature13152
  15. Rho, J., Takami, M., and Choi, Y. (2004). Osteoimmunology: interactions of the immune and skeletal systems. Mol. Cells 17, 1-9.
  16. Sasaki, H., Yamamoto, H., Tominaga, K., Masuda, K., Kawai, T., Teshima-Kondo, S., and Rokutan, K. (2009). NADPH oxidasederived reactive oxygen species are essential for differentiation of a mouse macrophage cell line (RAW264.7) into osteoclasts. J. Med. Invest. 56, 33-41. https://doi.org/10.2152/jmi.56.33
  17. Walsh, M.C., Kim, N., Kadono, Y., Rho, J., Lee, S.Y., Lorenzo, J., and Choi, Y. (2006). Osteoimmunology: interplay between the immune system and bone metabolism. Annu. Rev. Immunol. 24, 33-63. https://doi.org/10.1146/annurev.immunol.24.021605.090646
  18. Yamashita, T., Yao, Z., Li, F., Zhang, Q., Badell, I.R., Schwarz, E.M., Takeshita, S., Wagner, E.F., Noda, M., Matsuo, K., et al. (2007). NF-kappaB p50 and p52 regulate receptor activator of NFkappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. J. Biol. Chem. 282, 18245-18253. https://doi.org/10.1074/jbc.M610701200
  19. Zhou, J., Ye, S., Fujiwara, T., Manolagas, S.C., and Zhao, H. (2013). Steap4 plays a critical role in osteoclastogenesis in vitro by regulating cellular iron/reactive oxygen species (ROS) levels and cAMP response element-binding protein (CREB) activation. J. Biol. Chem. 288, 30064-30074. https://doi.org/10.1074/jbc.M113.478750

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