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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Tusc2/Fus1 regulates osteoclast differentiation through NF-κB and NFATc1

  • Kim, Inyoung (Department of Pharmacology, Chonnam National University Medical School) ;
  • Kim, Jung Ha (Department of Pharmacology, Chonnam National University Medical School) ;
  • Kim, Kabsun (Department of Pharmacology, Chonnam National University Medical School) ;
  • Seong, Semun (Department of Pharmacology, Chonnam National University Medical School) ;
  • Kim, Nacksung (Department of Pharmacology, Chonnam National University Medical School)
  • Received : 2017.02.18
  • Accepted : 2017.04.03
  • Published : 2017.09.30
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Abstract

Tumor suppressor candidate 2 (Tusc2, also known as Fus1) regulates calcium signaling, and $Ca^{2+}$-dependent nuclear factor of activated T-cells (NFAT) and nuclear factor kappa B ($NF-{\kappa}B$) pathways, which play roles in osteoclast differentiation. However, the role of Tusc2 in osteoclasts remains unknown. Here, we report that Tusc2 positively regulates the differentiation of osteoclasts. Overexpression of Tusc2 in osteoclast precursor cells enhanced receptor activator of nuclear factor ${\kappa}B$ ligand (RANKL)-induced osteoclast differentiation. In contrast, small interfering RNA-mediated knockdown of Tusc2 strongly inhibited osteoclast differentiation. In addition, Tusc2 induced the activation of RANKL-mediated $NF-{\kappa}B$ and calcium/calmodulin-dependent kinase IV (CaMKIV)/cAMP-response element (CRE)-binding protein CREB signaling cascades. Taken together, these results suggest that Tusc2 acts as a positive regulator of RANKL-mediated osteoclast differentiation.

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References

  1. Boyle WJ, Simonet WS and Lacey DL (2003) Osteoclast differentiation and activation. Nature 423, 337-342 https://doi.org/10.1038/nature01658
  2. Walsh MC, Kim N, Kadono Y et al (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
  3. Teitelbaum SL (2000) Bone resorption by osteoclasts. Science 289, 1504-1508 https://doi.org/10.1126/science.289.5484.1504
  4. Ogasawara T, Kawaguchi H, Jinno S et al (2004) Bone morphogenetic protein 2-induced osteoblast differentiation requires Smad-mediated down-regulation of Cdk6. Mol Cell Biol 24, 6560-6568 https://doi.org/10.1128/MCB.24.15.6560-6568.2004
  5. Kim JH and Kim N (2016) Signaling Pathways in Osteoclast Differentiation. Chonnam Med J 52, 12-17 https://doi.org/10.4068/cmj.2016.52.1.12
  6. Kim JH and Kim N (2014) Regulation of NFATc1 in Osteoclast Differentiation. J Bone Metab 21, 233-241 https://doi.org/10.11005/jbm.2014.21.4.233
  7. Kim K, Kim JH, Lee J et al (2005) Nuclear factor of activated T cells c1 induces osteoclast-associated receptor gene expression during tumor necrosis factor-related activation-induced cytokine-mediated osteoclastogenesis. J Biol Chem 280, 35209-35216 https://doi.org/10.1074/jbc.M505815200
  8. Kim K, Lee SH, 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
  9. Takayanagi H, Kim S, Koga T et al (2002) Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 3, 889-901 https://doi.org/10.1016/S1534-5807(02)00369-6
  10. Hwang SY and Putney JW Jr (2011) Calcium signaling in osteoclasts. Biochim Biophys Acta 1813, 979-983 https://doi.org/10.1016/j.bbamcr.2010.11.002
  11. Hogan PG, Chen L, Nardone J and Rao A (2003) Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev 17, 2205-2232 https://doi.org/10.1101/gad.1102703
  12. Racioppi L and Means AR (2008) Calcium/calmodulindependent kinase IV in immune and inflammatory responses: novel routes for an ancient traveller. Trends Immunol 29, 600-607 https://doi.org/10.1016/j.it.2008.08.005
  13. Sato K, Suematsu A, Nakashima T et al (2006) Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nat Med 12, 1410-1416 https://doi.org/10.1038/nm1515
  14. Ang ES, Zhang P, Steer JH et al (2007) Calcium/calmodulindependent kinase activity is required for efficient induction of osteoclast differentiation and bone resorption by receptor activator of nuclear factor kappa B ligand (RANKL). J Cell Physiol 212, 787-795 https://doi.org/10.1002/jcp.21076
  15. Krueger JK, Olah GA, Rokop SE, Zhi G, Stull JT and Trewhella J (1997) Structures of calmodulin and a functional myosin light chain kinase in the activated complex: a neutron scattering study. Biochemistry 36, 6017-6023 https://doi.org/10.1021/bi9702703
  16. Prudkin L, Behrens C, Liu DD et al (2008) Loss and reduction of FUS1 protein expression is a frequent phenomenon in the pathogenesis of lung cancer. Clin Cancer Res 14, 41-47 https://doi.org/10.1158/1078-0432.CCR-07-1252
  17. Ivanova AV, Ivanov SV, Prudkin L et al (2009) Mechanisms of FUS1/TUSC2 deficiency in mesothelioma and its tumorigenic transcriptional effects. Mol Cancer 8, 91 https://doi.org/10.1186/1476-4598-8-91
  18. Li G, Kawashima H, Ji L et al (2011) Frequent absence of tumor suppressor FUS1 protein expression in human bone and soft tissue sarcomas. Anticancer Res 31, 11-21
  19. Uzhachenko R, Ivanov SV, Yarbrough WG, Shanker A, Medzhitov R and Ivanova AV (2014) Fus1/Tusc2 is a novel regulator of mitochondrial calcium handling, Ca2+-coupled mitochondrial processes, and Ca2+-dependent NFAT and NF-kappaB pathways in CD4+ T cells. Antioxid Redox Signal 20, 1533-1547 https://doi.org/10.1089/ars.2013.5437
  20. Kim K, Kim JH, Youn BU, Jin HM and Kim N (2010) Pim-1 regulates RANKL-induced osteoclastogenesis via NF-kappaB activation and NFATc1 induction. J Immunol 185, 7460-7466 https://doi.org/10.4049/jimmunol.1000885
  21. Kajiya H (2012) Calcium signaling in osteoclast differentiation and bone resorption. Adv Exp Med Biol 740, 917-932
  22. Uzhachenko R, Shanker A, Yarbrough WG and Ivanova AV (2015) Mitochondria, calcium, and tumor suppressor Fus1: At the crossroad of cancer, inflammation, and autoimmunity. Oncotarget 6, 20754-20772 https://doi.org/10.18632/oncotarget.4537
  23. Takami M, Woo JT, Takahashi N, Suda T and Nagai K (1997) Ca2+-ATPase inhibitors and Ca2+-ionophore induce osteoclast-like cell formation in the cocultures of mouse bone marrow cells and calvarial cells. Biochem Biophys Res Commun 237, 111-115 https://doi.org/10.1006/bbrc.1997.7090
  24. Franzoso G, Carlson L, Xing L et al (1997) Requirement for NF-kappaB in osteoclast and B-cell development. Genes Dev 11, 3482-3496 https://doi.org/10.1101/gad.11.24.3482
  25. Takatsuna H, Asagiri M, Kubota T et al (2005) Inhibition of RANKL-induced osteoclastogenesis by (-)-DHMEQ, a novel NF-kappaB inhibitor, through downregulation of NFATc1. J Bone Miner Res 20, 653-662
  26. Asagiri M, Sato K, Usami T et al (2005) Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med 202, 1261-1269 https://doi.org/10.1084/jem.20051150
  27. Dolmetsch RE, Lewis RS, Goodnow CC and Healy JI (1997) Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 386, 855-858 https://doi.org/10.1038/386855a0
  28. Lilienbaum A and Israel A (2003) From calcium to NF-kappa B signaling pathways in neurons. Mol Cell Biol 23, 2680-2698 https://doi.org/10.1128/MCB.23.8.2680-2698.2003
  29. Tabary O, Boncoeur E, de Martin R et al (2006) Calciumdependent regulation of NF-(kappa)B activation in cystic fibrosis airway epithelial cells. Cell Signal 18, 652-660 https://doi.org/10.1016/j.cellsig.2005.06.004
  30. Boland ML, Chourasia AH and Macleod KF (2013) Mitochondrial dysfunction in cancer. Front Oncol 3, 292
  31. Boyce BF, Xiu Y, Li J, Xing L and Yao Z (2015) NF-kappaB-mediated regulation of osteoclastogenesis. Endocrinol Metab (Seoul) 30, 35-44 https://doi.org/10.3803/EnM.2015.30.1.35
  32. Park HJ, Baek K, Baek JH and Kim HR (2015) The cooperation of CREB and NFAT is required for PTHrPinduced RANKL expression in mouse osteoblastic cells. J Cell Physiol 230, 667-679 https://doi.org/10.1002/jcp.24790
  33. Kim K, Kim JH, Lee J et al (2007) MafB negatively regulates RANKL-mediated osteoclast differentiation. Blood 109, 3253-3259 https://doi.org/10.1182/blood-2006-09-048249
  34. Song I, Jeong BC, Choi YJ, Chung YS, Kim N (2016) GATA4 negatively regulates bone sialoprotein expression in osteoblasts. BMB Rep 49, 343-348 https://doi.org/10.5483/BMBRep.2016.49.6.032

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