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A novel role of l-serine (l-Ser) for the expression of nuclear factor of activated T cells (NFAT)2 in receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis in vitro

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Abstract

Multinucleated cell formation is crucial for osteoclastogenesis, and the expression of nuclear factor of activated T cells (NFAT)2 (NFATc1) is essential for this process. We previously found, using mouse RAW264 cells, that culture at high cell density blocked progression to the multinucleated cell stage induced by stimulation with receptor activator of nuclear factor κB ligand (RANKL). Here, we have confirmed this finding in a bone marrow cell system and extended the analysis further. A high cell density appeared to cause a change in the composition of the culture medium accompanying downregulation of NFAT2 expression, and we identified l-serine (l-Ser) as essential for the expression of NFAT2 induced by RANKL. Namely, culture at high cell density caused a depletion of l-Ser in the medium. Consequently, l-Ser appeared to exert its effect at an early stage under the regular conditions used for inducing the expression of c-Fos, an upstream regulator of NFAT2. d-Ser, an enantiomer of l-Ser, showed no NFAT2-inducing activity. The expression of NFAT2, using a retrovirus vector, could compensate for the depletion of l-Ser and resume the progression to the multinucleated cell stage. These results demonstrate a novel role for l-Ser in RANKL-induced osteoclastogenesis in vitro.

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References

  1. GD Roodman (1996) ArticleTitleAdvances in bone biology: the osteoclast Endocr Rev 17 308–332 Occurrence Handle8854048 Occurrence Handle1:CAS:528:DyaK28Xltl2mtrY%3D Occurrence Handle10.1210/er.17.4.308

    Article  PubMed  CAS  Google Scholar 

  2. SL Teitelbaum (2000) ArticleTitleBone resorption by osteoclasts Science 289 1504–1508 Occurrence Handle10968780 Occurrence Handle1:CAS:528:DC%2BD3cXmt1KgsLk%3D Occurrence Handle10.1126/science.289.5484.1504

    Article  PubMed  CAS  Google Scholar 

  3. WJ Boyle WS Simonet DL Lacey (2003) ArticleTitleOsteoclast differentiation and activation Nature 423 337–342 Occurrence Handle12748652 Occurrence Handle1:CAS:528:DC%2BD3sXjs1ynu7g%3D Occurrence Handle10.1038/nature01658

    Article  PubMed  CAS  Google Scholar 

  4. S Tanaka K Nakamura N Takahashi T Suda (2005) ArticleTitleRole of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system Immunol Rev 208 30–49 Occurrence Handle16313339 Occurrence Handle1:CAS:528:DC%2BD28Xks1ejuw%3D%3D Occurrence Handle10.1111/j.0105-2896.2005.00327.x

    Article  PubMed  CAS  Google Scholar 

  5. N Ishida K Hayashi M Hoshijima T Ogawa S Koga Y Miyatake M Kumegawa T Kimura T Takeya (2002) ArticleTitleLarge scale gene expression analysis of osteoclastogenesis in vitro and elucidation of NFAT2 as a key regulator J Biol Chem 277 41 147–41 156 Occurrence Handle1:CAS:528:DC%2BD38XnvFymsL0%3D

    CAS  Google Scholar 

  6. H Takayanagi S Kim T Koga H Nishina M Isshiki H Yoshida A Saiura M Isobe T Yokochi J Inoue EF Wagner TW Mak T Kodama T Taniguchi (2002) ArticleTitleInduction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts Dev Cell 3 889–901 Occurrence Handle12479813 Occurrence Handle1:CAS:528:DC%2BD38XpslClsL8%3D Occurrence Handle10.1016/S1534-5807(02)00369-6

    Article  PubMed  CAS  Google Scholar 

  7. K Matsuo DL Galson C Zhao L Peng C Laplace KZQ Wang MA Bachler H Amano H Aburatani H Ishikawa EF Wagner (2004) ArticleTitleNuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos J Biol Chem 279 26 475–26 480 Occurrence Handle1:CAS:528:DC%2BD2cXkvVWgtr4%3D Occurrence Handle10.1074/jbc.M313973200

    Article  CAS  Google Scholar 

  8. V Tropepe S Hitoshi C Sirard TW Mak J Rossant D van der Kooy (2001) ArticleTitleDirect neural fate specification from embryonic stem cells: a primitive mammalian neural stem cell stage acquired through a default mechanism Neuron 30 65–78 Occurrence Handle11343645 Occurrence Handle1:CAS:528:DC%2BD3MXjsVCiurg%3D Occurrence Handle10.1016/S0896-6273(01)00263-X

    Article  PubMed  CAS  Google Scholar 

  9. QL Ying M Stavridis D Griffiths M Li A Smith (2003) ArticleTitleConversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture Nat Biotechnol 21 183–186 Occurrence Handle12524553 Occurrence Handle1:CAS:528:DC%2BD3sXnsFWitQ%3D%3D Occurrence Handle10.1038/nbt780

    Article  PubMed  CAS  Google Scholar 

  10. GR Merlo F Basolo L Fiore L Duboc NE Hynes (1995) ArticleTitlep53-Dependent and p53-independent activation of apoptosis in mammary epithelial cells reveals a survival function of EGF and insulin J Cell Biol 128 1185–1196 Occurrence Handle7896881 Occurrence Handle1:CAS:528:DyaK2MXktlKls7Y%3D Occurrence Handle10.1083/jcb.128.6.1185

    Article  PubMed  CAS  Google Scholar 

  11. JJ Otero W Fu L Kan AE Cuadra JA Kessler (2004) ArticleTitleb-Catenin signaling is required for neural differentiation of embryonic stem cells Development 131 3545–3557 Occurrence Handle15262888 Occurrence Handle1:CAS:528:DC%2BD2cXnt1eltr0%3D Occurrence Handle10.1242/dev.01218

    Article  PubMed  CAS  Google Scholar 

  12. PY Desprez E Hara MJ Bissell J Campisi (1995) ArticleTitleSuppression of mammary epithelial cell differentiation by the helix-loop-helix protein Id-1 Mol Cell Biol 15 3398–3404 Occurrence Handle7760836 Occurrence Handle1:CAS:528:DyaK2MXlslyiu7s%3D

    PubMed  CAS  Google Scholar 

  13. E Meiyanto M Hoshijima T Ogawa N Ishida T Takeya (2001) ArticleTitleOsteoclast differentiation factor modulates cell cycle machinery and causes a delay in S phase progression in RAW264 cells Biochem Biophys Res Commun 282 278–283 Occurrence Handle11264004 Occurrence Handle1:CAS:528:DC%2BD3MXitFeitL8%3D Occurrence Handle10.1006/bbrc.2001.4564

    Article  PubMed  CAS  Google Scholar 

  14. N Ishida K Hayashi A Hattori K Yogo T Kimura T Takeya (2006) ArticleTitleCCR1 acts downstream of NFAT2 in osteoclastogenesis and enhances cell migration J Bone Miner Res 21 48–57 Occurrence Handle16355273 Occurrence Handle1:CAS:528:DC%2BD28Xpt1SntQ%3D%3D Occurrence Handle10.1359/JBMR.051001

    Article  PubMed  CAS  Google Scholar 

  15. T Akagi K Sasai H Hanafusa (2003) ArticleTitleRefractory nature of normal human diploid fibroblasts with respect to oncogene-mediated transformation Proc Natl Acad Sci USA 100 13 567–13 572 Occurrence Handle1:CAS:528:DC%2BD3sXptFOitL4%3D Occurrence Handle10.1073/pnas.1834876100

    Article  CAS  Google Scholar 

  16. S Morita T Kojima T Kitamura (2000) ArticleTitlePlat-E: an efficient and stable system for transient packaging of retroviruses Gene Ther 7 1063–1066 Occurrence Handle10871756 Occurrence Handle1:CAS:528:DC%2BD3cXkt1amtr0%3D Occurrence Handle10.1038/sj.gt.3301206

    Article  PubMed  CAS  Google Scholar 

  17. R Curi CJ Lagranha SQ Doi DF Sellitti J Procopio TC Pithon-Curi M Corless P Newsholme (2005) ArticleTitleMolecular mechanisms of glutamine action J Cell Physiol 204 392–401 Occurrence Handle15795900 Occurrence Handle1:CAS:528:DC%2BD2MXlvFCrs7w%3D Occurrence Handle10.1002/jcp.20339

    Article  PubMed  CAS  Google Scholar 

  18. TJ de Koning K Snell M Duran R Berger BT Poll-The R Surtees (2003) ArticleTitleL-Serine in disease and development Biochem J 371 653–661 Occurrence Handle12534373 Occurrence Handle1:CAS:528:DC%2BD3sXjtFKmurs%3D Occurrence Handle10.1042/BJ20021785

    Article  PubMed  CAS  Google Scholar 

  19. Nakanishi N, Shneider NA, Axel R (1990) Neuron A family of glutamate receptor genes: evidence for the formation of heteromultimeric receptors with distinct channel properties. 5:569–581

  20. J Pláteník N Kuramoto Y Yoneda (2000) ArticleTitleMolecular mechanisms associated with long-term consolidation of the NMDA signals Life Sci 67 335–364 Occurrence Handle11003045 Occurrence Handle10.1016/S0024-3205(00)00632-9

    Article  PubMed  Google Scholar 

  21. S Furuya T Tabata J Mitoma K Yamada M Yamasaki A Makino T Yamamoto M Watanabe Y Hirabayashi (2000) ArticleTitleL-Serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons Proc Natl Acad Sci USA 97 11 528–11 533 Occurrence Handle1:CAS:528:DC%2BD3cXnsF2qsLw%3D

    CAS  Google Scholar 

  22. LWJ Klomp TJ de Koning HEM Malingré EACM van Beurden M Brink FL Opdam M Duran J Jaeken M Pineda L van Maldergem BT Poll-The IET van den Berg R Berger (2000) ArticleTitleMolecular characterization of 3-phosphoglycerate dehydrogenase deficiency – a neurometabolic disorder associated with reduced l-serine biosynthesis Am J Hum Genet 67 1389–1399 Occurrence Handle11055895 Occurrence Handle1:CAS:528:DC%2BD3cXovVKju74%3D Occurrence Handle10.1086/316886

    Article  PubMed  CAS  Google Scholar 

  23. J Jaeken M Detheux L Van Maldergem M Foulon H Carchon E Van Schaftingen (1996) ArticleTitle3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis Arch Dis Child 74 542–545 Occurrence Handle8758134 Occurrence Handle1:STN:280:BymA3MfntVc%3D Occurrence Handle10.1136/adc.74.6.542

    Article  PubMed  CAS  Google Scholar 

  24. K Yoshida S Furuya S Osuka J Mitoma Y Shinoda M Watanabe N Azuma H Tanaka T Hashikawa S Itohara Y Hirabayashi (2004) ArticleTitleTargeted disruption of the mouse 3-phosphoglycerate dehydrogenase gene causes severe neurodevelopmental defects and results in embryonic lethality J Biol Chem 279 3573–3577 Occurrence Handle14645240 Occurrence Handle1:CAS:528:DC%2BD2cXmtlCltg%3D%3D Occurrence Handle10.1074/jbc.C300507200

    Article  PubMed  CAS  Google Scholar 

  25. S Tanaka I Nakamura J Inoue H Oda K Nakamura (2003) ArticleTitleSignal transduction pathways regulating osteoclast differentiation and function J Bone Miner Metab 21 123–133 Occurrence Handle12720046 Occurrence Handle10.1007/s007740300021

    Article  PubMed  Google Scholar 

  26. ZH Lee HH Kim (2003) ArticleTitleSignal transduction by receptor activator of nuclear factor kappa B in osteoclasts Biochem Biophys Res Commun 305 211–214 Occurrence Handle12745060 Occurrence Handle1:CAS:528:DC%2BD3sXjs1ert7g%3D Occurrence Handle10.1016/S0006-291X(03)00695-8

    Article  PubMed  CAS  Google Scholar 

  27. S Fujioka J Niu C Schmidt GM Sclabas B Peng T Uwagawa Z Li DB Evans JL Abbruzzese PJ Chiao (2004) ArticleTitleNF-kappaB and AP-1 connection: mechanism of NF-kappaB-dependent regulation of AP-1 activity Mol Cell Biol 24 7806–7819 Occurrence Handle15314185 Occurrence Handle1:CAS:528:DC%2BD2cXntVKgsr8%3D Occurrence Handle10.1128/MCB.24.17.7806-7819.2004

    Article  PubMed  CAS  Google Scholar 

  28. M Piechaczyk JM Blanchard (1994) ArticleTitlec-fos Proto-oncogene regulation and function Crit Rev Oncol Hematol 17 93–131 Occurrence Handle7818789 Occurrence Handle1:STN:280:ByqC3MfltV0%3D

    PubMed  CAS  Google Scholar 

  29. M Karin Z Liu E Zandi (1997) ArticleTitleAP-1 function and regulation Curr Opin Cell Biol 9 240–246 Occurrence Handle9069263 Occurrence Handle1:CAS:528:DyaK2sXisVWlsL0%3D Occurrence Handle10.1016/S0955-0674(97)80068-3

    Article  PubMed  CAS  Google Scholar 

  30. Y Ito D Inoue S Kido T Matsumoto (2005) ArticleTitlec-Fos degradation by the ubiquitin-proteasome proteolytic pathway in osteoclast progenitors Bone 37 842–849 Occurrence Handle16172035 Occurrence Handle1:CAS:528:DC%2BD2MXhtlShsrbE Occurrence Handle10.1016/j.bone.2005.04.030

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara, 630-0101, Japan

    Takuya Ogawa, Norihiro Ishida-Kitagawa, Akira Tanaka, Takahiro Matsumoto, Tamayo Hirouchi, Mai Akimaru, Keiichiro Yogo & Tatsuo Takeya

  2. Graduate School of Materials Science, Nara Institute of Science and Technology, Ikoma, Nara, Japan

    Masao Tanihara

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  1. Takuya Ogawa
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  2. Norihiro Ishida-Kitagawa
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Correspondence to Tatsuo Takeya.

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Ogawa, T., Ishida-Kitagawa, N., Tanaka, A. et al. A novel role of l-serine (l-Ser) for the expression of nuclear factor of activated T cells (NFAT)2 in receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis in vitro. J Bone Miner Metab 24, 373–379 (2006). https://doi.org/10.1007/s00774-006-0705-0

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  • DOI: https://doi.org/10.1007/s00774-006-0705-0

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