Advertisement

Adaptive Immune Responses and Bone

  • Hiroshi Takayanagi
Conference paper

Abstract

Effects of the adaptive immune responses on bone have been the central issue in rheumatoid arthritis research, which promoted the development of osteoimmunology. Bone destruction associated with arthritis is caused by the enhanced activity of osteoclasts, resulting from the activation of a unique helper T cell subset “Th17 cells.” The better understanding of the molecular mechanism of Th17 development will lead to the development of potentially effective therapeutic strategies.

Keywords

Rheumatoid Arthritis Patient Th17 Cell Treg Cell Bone Destruction Osteoclast Differentiation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

I am grateful to Dr. Kazuo Okamoto for the assistance in preparing the manuscript. This work was supported in part by Grants-in-Aid for GCOE Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), and ERATO, Takayanagi Osteonetwork Project from JST.

References

  1. 1.
    Seeman E, Delmas PD (2006) Bone quality – the material and structural basis of bone strength and fragility. N Engl J Med 354(21):2250–2261PubMedCrossRefGoogle Scholar
  2. 2.
    Takayanagi H (2007) Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol 7(4):292–304PubMedCrossRefGoogle Scholar
  3. 3.
    Takahashi N, Akatsu T, Udagawa N, Sasaki T, Yamaguchi A, Moseley JM, Martin TJ, Suda T (1988) Osteoblastic cells are involved in osteoclast formation. Endocrinology 123(5):2600–2602PubMedCrossRefGoogle Scholar
  4. 4.
    Takahashi N, Yamana H, Yoshiki S, Roodman GD, Mundy GR, Jones SJ, Boyde A, Suda T (1988) Osteoclast-like cell formation and its regulation by osteotropic hormones in mouse bone marrow cultures. Endocrinology 122(4):1373–1382PubMedCrossRefGoogle Scholar
  5. 5.
    Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ (1999) Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev 20(3):345–357PubMedCrossRefGoogle Scholar
  6. 6.
    Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD (1990) The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345(6274):442–444PubMedCrossRefGoogle Scholar
  7. 7.
    Lagasse E, Weissman IL (1997) Enforced expression of Bcl-2 in monocytes rescues macrophages and partially reverses osteopetrosis in op/op mice. Cell 89(7):1021–1031PubMedCrossRefGoogle Scholar
  8. 8.
    Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A et al (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 95(7):3597–3602PubMedCrossRefGoogle Scholar
  9. 9.
    Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S et al (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93(2):165–176PubMedCrossRefGoogle Scholar
  10. 10.
    Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L (1997) A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390(6656):175–179PubMedCrossRefGoogle Scholar
  11. 11.
    Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett FS 3rd, Frankel WN et al (1997) TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J Biol Chem 272(40):25190–25194PubMedCrossRefGoogle Scholar
  12. 12.
    Theill LE, Boyle WJ, Penninger JM (2002) RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu Rev Immunol 20:795–823PubMedCrossRefGoogle Scholar
  13. 13.
    Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T et al (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89(2):309–319PubMedCrossRefGoogle Scholar
  14. 14.
    Tsuda E, Goto M, Mochizuki S, Yano K, Kobayashi F, Morinaga T, Higashio K (1997) Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem Biophys Res Commun 234(1):137–142PubMedCrossRefGoogle Scholar
  15. 15.
    Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A et al (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397(6717):315–323PubMedCrossRefGoogle Scholar
  16. 16.
    Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T, Daro E, Smith J, Tometsko ME, Maliszewski CR et al (1999) RANK is essential for osteoclast and lymph node development. Genes Dev 13(18):2412–2424PubMedCrossRefGoogle Scholar
  17. 17.
    Li J, Sarosi I, Yan XQ, Morony S, Capparelli C, Tan HL, McCabe S, Elliott R, Scully S, Van G et al (2000) RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA 97(4):1566–1571PubMedCrossRefGoogle Scholar
  18. 18.
    Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL et al (1998) osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12(9):1260–1268PubMedCrossRefGoogle Scholar
  19. 19.
    Mizuno A, Amizuka N, Irie K, Murakami A, Fujise N, Kanno T, Sato Y, Nakagawa N, Yasuda H, Mochizuki S et al (1998) Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun 247(3):610–615PubMedCrossRefGoogle Scholar
  20. 20.
    Hughes AE, Ralston SH, Marken J, Bell C, MacPherson H, Wallace RG, van Hul W, Whyte MP, Nakatsuka K, Hovy L et al (2000) Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet 24(1):45–48PubMedCrossRefGoogle Scholar
  21. 21.
    Whyte MP, Obrecht SE, Finnegan PM, Jones JL, Podgornik MN, McAlister WH, Mumm S (2002) Osteoprotegerin deficiency and juvenile Paget’s disease. N Engl J Med 347(3):175–184PubMedCrossRefGoogle Scholar
  22. 22.
    Sobacchi C, Frattini A, Guerrini MM, Abinun M, Pangrazio A, Susani L, Bredius R, Mancini G, Cant A, Bishop N et al (2007) Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet 39(8):960–962PubMedCrossRefGoogle Scholar
  23. 23.
    Guerrini MM, Sobacchi C, Cassani B, Abinun M, Kilic SS, Pangrazio A, Moratto D, Mazzolari E, Clayton-Smith J, Orchard P et al (2008) Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. Am J Hum Genet 83(1):64–76PubMedCrossRefGoogle Scholar
  24. 24.
    Lomaga MA, Yeh WC, Sarosi I, Duncan GS, Furlonger C, Ho A, Morony S, Capparelli C, Van G, Kaufman S et al (1999) TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev 13(8):1015–1024PubMedCrossRefGoogle Scholar
  25. 25.
    Naito A, Azuma S, Tanaka S, Miyazaki T, Takaki S, Takatsu K, Nakao K, Nakamura K, Katsuki M, Yamamoto T et al (1999) Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 4(6):353–362PubMedCrossRefGoogle Scholar
  26. 26.
    Wagner EF, Eferl R (2005) Fos/AP-1 proteins in bone and the immune system. Immunol Rev 208:126–140PubMedCrossRefGoogle Scholar
  27. 27.
    Sato K, Suematsu A, Nakashima T, Takemoto-Kimura S, Aoki K, Morishita Y, Asahara H, Ohya K, Yamaguchi A, Takai T et al (2006) Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nat Med 12(12):1410–1416PubMedCrossRefGoogle Scholar
  28. 28.
    Yamashita T, Yao Z, Li F, Zhang Q, Badell IR, Schwarz EM, Takeshita S, Wagner EF, Noda M, Matsuo K et al (2007) NF-κB p50 and p52 regulate receptor activator of NF-κB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. J Biol Chem 282(25):18245–18253PubMedCrossRefGoogle Scholar
  29. 29.
    Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M, Yokochi T, Inoue J et al (2002) Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 3(6):889–901PubMedCrossRefGoogle Scholar
  30. 30.
    Asagiri M, Sato K, Usami T, Ochi S, Nishina H, Yoshida H, Morita I, Wagner EF, Mak TW, Serfling E et al (2005) Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med 202(9):1261–1269PubMedCrossRefGoogle Scholar
  31. 31.
    Winslow MM, Pan M, Starbuck M, Gallo EM, Deng L, Karsenty G, Crabtree GR (2006) Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev Cell 10(6):771–782PubMedCrossRefGoogle Scholar
  32. 32.
    Aliprantis AO, Ueki Y, Sulyanto R, Park A, Sigrist KS, Sharma SM, Ostrowski MC, Olsen BR, Glimcher LH (2008) NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism. J Clin Invest 118(11):3775–3789PubMedCrossRefGoogle Scholar
  33. 33.
    Koga T, Inui M, Inoue K, Kim S, Suematsu A, Kobayashi E, Iwata T, Ohnishi H, Matozaki T, Kodama T et al (2004) Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428(6984):758–763PubMedCrossRefGoogle Scholar
  34. 34.
    Mocsai A, Humphrey MB, Van Ziffle JA, Hu Y, Burghardt A, Spusta SC, Majumdar S, Lanier LL, Lowell CA, Nakamura MC (2004) The immunomodulatory adapter proteins DAP12 and Fc receptor γ-chain (FcRγ) regulate development of functional osteoclasts through the Syk tyrosine kinase. Proc Natl Acad Sci USA 101(16):6158–6163PubMedCrossRefGoogle Scholar
  35. 35.
    Shinohara M, Koga T, Okamoto K, Sakaguchi S, Arai K, Yasuda H, Takai T, Kodama T, Morio T, Geha RS et al (2008) Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell 132(5):794–806PubMedCrossRefGoogle Scholar
  36. 36.
    Bromley M, Woolley DE (1984) Chondroclasts and osteoclasts at subchondral sites of erosion in the rheumatoid joint. Arthritis Rheum 27(9):968–975PubMedCrossRefGoogle Scholar
  37. 37.
    Takayanagi H, Oda H, Yamamoto S, Kawaguchi H, Tanaka S, Nishikawa T, Koshihara Y (1997) A new mechanism of bone destruction in rheumatoid arthritis: synovial fibroblasts induce osteoclastogenesis. Biochem Biophys Res Commun 240(2):279–286PubMedCrossRefGoogle Scholar
  38. 38.
    Gravallese EM, Manning C, Tsay A, Naito A, Pan C, Amento E, Goldring SR (2000) Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum 43(2):250–258PubMedCrossRefGoogle Scholar
  39. 39.
    Takayanagi H, Iizuka H, Juji T, Nakagawa T, Yamamoto A, Miyazaki T, Koshihara Y, Oda H, Nakamura K, Tanaka S (2000) Involvement of receptor activator of nuclear factor κB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum 43(2):259–269PubMedCrossRefGoogle Scholar
  40. 40.
    Pettit AR, Ji H, von Stechow D, Muller R, Goldring SR, Choi Y, Benoist C, Gravallese EM (2001) TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am J Pathol 159(5):1689–1699PubMedCrossRefGoogle Scholar
  41. 41.
    Redlich K, Hayer S, Ricci R, David JP, Tohidast-Akrad M, Kollias G, Steiner G, Smolen JS, Wagner EF, Schett G (2002) Osteoclasts are essential for TNF-α-mediated joint destruction. J Clin Invest 110(10):1419–1427PubMedGoogle Scholar
  42. 42.
    Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, Capparelli C, Li J, Elliott R, McCabe S et al (1999) Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402(6759):304–309PubMedCrossRefGoogle Scholar
  43. 43.
    Takayanagi H, Juji T, Miyazaki T, Iizuka H, Takahashi T, Isshiki M, Okada M, Tanaka Y, Koshihara Y, Oda H et al (1999) Suppression of arthritic bone destruction by adenovirus-mediated csk gene transfer to synoviocytes and osteoclasts. J Clin Invest 104(2):137–146PubMedCrossRefGoogle Scholar
  44. 44.
    Takayanagi H (2009) Osteoimmunology and the effects of the immune system on bone. Nat Rev Rheumatol 5(12):667–676PubMedCrossRefGoogle Scholar
  45. 45.
    Horwood NJ, Kartsogiannis V, Quinn JM, Romas E, Martin TJ, Gillespie MT (1999) Activated T lymphocytes support osteoclast formation in vitro. Biochem Biophys Res Commun 265(1):144–150PubMedCrossRefGoogle Scholar
  46. 46.
    Zhou L, Chong MM, Littman DR (2009) Plasticity of CD4+ T cell lineage differentiation. Immunity 30(5):646–655PubMedCrossRefGoogle Scholar
  47. 47.
    Firestein GS, Zvaifler NJ (1990) How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum 33(6):768–773PubMedCrossRefGoogle Scholar
  48. 48.
    Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, Takaoka A, Yokochi T, Oda H, Tanaka K et al (2000) T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. Nature 408(6812):600–605PubMedCrossRefGoogle Scholar
  49. 49.
    Manoury-Schwartz B, Chiocchia G, Bessis N, Abehsira-Amar O, Batteux F, Muller S, Huang S, Boissier MC, Fournier C (1997) High susceptibility to collagen-induced arthritis in mice lacking IFN-γ receptors. J Immunol 158(11):5501–5506PubMedGoogle Scholar
  50. 50.
    Vermeire K, Heremans H, Vandeputte M, Huang S, Billiau A, Matthys P (1997) Accelerated collagen-induced arthritis in IFN-γ receptor-deficient mice. J Immunol 158(11):5507–5513PubMedGoogle Scholar
  51. 51.
    Sato K, Takayanagi H (2006) Osteoclasts, rheumatoid arthritis, and osteoimmunology. Curr Opin Rheumatol 18(4):419–426PubMedCrossRefGoogle Scholar
  52. 52.
    Kastelein RA, Hunter CA, Cua DJ (2007) Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol 25:221–242PubMedCrossRefGoogle Scholar
  53. 53.
    Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 cells. Annu Rev Immunol 27:485–517PubMedCrossRefGoogle Scholar
  54. 54.
    Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, Tanaka S, Kodama T, Akira S, Iwakura Y et al (2006) Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med 203(12):2673–2682PubMedCrossRefGoogle Scholar
  55. 55.
    Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, Saito S, Inoue K, Kamatani N, Gillespie MT et al (1999) IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 103(9):1345–1352PubMedCrossRefGoogle Scholar
  56. 56.
    Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133(5):775–787PubMedCrossRefGoogle Scholar
  57. 57.
    Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, Mauri C (2004) Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFα therapy. J Exp Med 200(3):277–285PubMedCrossRefGoogle Scholar
  58. 58.
    Boissier MC, Assier E, Falgarone G, Bessis N (2008) Shifting the imbalance from Th1/Th2 to Th17/treg: the changing rheumatoid arthritis paradigm. Joint Bone Spine 75(4):373–375PubMedCrossRefGoogle Scholar
  59. 59.
    Nistala K, Wedderburn LR (2009) Th17 and regulatory T cells: rebalancing pro- and anti-inflammatory forces in autoimmune arthritis. Rheumatology (Oxford) 48(6):602–606CrossRefGoogle Scholar
  60. 60.
    Zaiss MM, Frey B, Hess A, Zwerina J, Luther J, Nimmerjahn F, Engelke K, Kollias G, Hunig T, Schett G et al (2010) Regulatory T cells protect from local and systemic bone destruction in arthritis. J Immunol 184(12):7238–7246PubMedCrossRefGoogle Scholar
  61. 61.
    Kim YG, Lee CK, Nah SS, Mun SH, Yoo B, Moon HB (2007) Human CD4+CD25+ regulatory T cells inhibit the differentiation of osteoclasts from peripheral blood mononuclear cells. Biochem Biophys Res Commun 357(4):1046–1052PubMedCrossRefGoogle Scholar
  62. 62.
    Zaiss MM, Axmann R, Zwerina J, Polzer K, Guckel E, Skapenko A, Schulze-Koops H, Horwood N, Cope A, Schett G (2007) Treg cells suppress osteoclast formation: a new link between the immune system and bone. Arthritis Rheum 56(12):4104–4112PubMedCrossRefGoogle Scholar
  63. 63.
    Zaiss MM, Sarter K, Hess A, Engelke K, Bohm C, Nimmerjahn F, Voll R, Schett G, David JP (2010) Increased bone density and resistance to ovariectomy-induced bone loss in FoxP3-transgenic mice based on impaired osteoclast differentiation. Arthritis Rheum 62(8):2328–2338PubMedCrossRefGoogle Scholar
  64. 64.
    Luo CY, Wang L, Sun C, Li DJ (2011) Estrogen enhances the functions of CD4+CD25+Foxp3+ regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro. Cell Mol Immunol 8(1):50–58PubMedCrossRefGoogle Scholar
  65. 65.
    Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126(6):1121–1133PubMedCrossRefGoogle Scholar
  66. 66.
    Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, Ma L, Shah B, Panopoulos AD, Schluns KS et al (2008) T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ. Immunity 28(1):29–39PubMedCrossRefGoogle Scholar
  67. 67.
    Okamoto K, Iwai Y, Oh-hora M, Yamamoto M, Morio T, Aoki K, Ohya K, Jetten AM, Akira S, Muta T et al (2010) IκBζ regulates TH17 development by cooperating with ROR nuclear receptors. Nature 464(7293):1381–1385PubMedCrossRefGoogle Scholar
  68. 68.
    Muta T (2006) IκB-ζ: an inducible regulator of nuclear factor-κB. Vitam Horm 74:301–316PubMedCrossRefGoogle Scholar
  69. 69.
    Yamamoto M, Yamazaki S, Uematsu S, Sato S, Hemmi H, Hoshino K, Kaisho T, Kuwata H, Takeuchi O, Takeshige K et al (2004) Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IκBζ. Nature 430(6996):218–222PubMedCrossRefGoogle Scholar
  70. 70.
    Brustle A, Heink S, Huber M, Rosenplanter C, Stadelmann C, Yu P, Arpaia E, Mak TW, Kamradt T, Lohoff M (2007) The development of inflammatory TH-17 cells requires interferon-regulatory factor 4. Nat Immunol 8(9):958–966PubMedCrossRefGoogle Scholar
  71. 71.
    Zhang F, Meng G, Strober W (2008) Interactions among the transcription factors Runx1, RORγt and Foxp3 regulate the differentiation of interleukin 17-producing T cells. Nature Immunol 9(11):1297–1306CrossRefGoogle Scholar
  72. 72.
    Akimzhanov AM, Yang XO, Dong C (2007) Chromatin remodeling of interleukin-17 (IL-17)-IL-17F cytokine gene locus during inflammatory helper T cell differentiation. J Biol Chem 282(9):5969–5972PubMedCrossRefGoogle Scholar
  73. 73.
    Takatori H, Kanno Y, Chen Z, O’Shea JJ (2008) New complexities in helper T cell fate determination and the implications for autoimmune diseases. Mod Rheumatol 18(6):533–541PubMedCrossRefGoogle Scholar
  74. 74.
    Mihara M, Ohsugi Y, Kishimoto T (2009) Evidence for the role of Th17 cell inhibition in the prevention of autoimmune diseases by anti-interluekin-6 receptor antibody. Biofactors 35(1):47–51PubMedCrossRefGoogle Scholar

Copyright information

© Springer New York 2013

Authors and Affiliations

  1. 1.Department of Cell Signaling, Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
  2. 2.Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone DiseasesTokyoJapan
  3. 3.Japan Science and Technology Agency (JST), ERATO, Takayanagi Osteonetwork ProjectTokyoJapan

Personalised recommendations