Journal of Clinical Immunology

, 29:555 | Cite as

Osteoimmunology: Crosstalk Between the Immune and Bone Systems

Article

Abstract

Introduction

The interaction between the immune and skeletal systems has long been acknowledged, but investigation into rheumatoid arthritis (RA) as well as the various bone phenotypes found in immunocompromised gene-deficient mice has highlighted the importance of the dynamic interplay between the two systems. This has led to the recent emergence and subsequent rapid evolution of the field of osteoimmunology.

Bone Destruction with Arthritis as a RANKL Disease

In the bone destruction associated with RA, IL-17-producing helper T cells (TH17) play a major role by inducing receptor activator of nuclear factor-κB ligand (RANKL). RANKL stimulates osteoclastogenesis through nuclear factor of activated T cells cytoplasmic 1 (NFATc1), which is well known as a crucial regulator of immunity.

New Players in Osteoimmunology

In addition to cellular interactions via cytokines, the immune and skeletal systems share various molecules, including transcription factors, signaling molecules, and membrane receptors.

Conclusion

The scope of osteoimmunology has grown to encompass a wide range of molecular and cellular interactions, the elucidation of which will provide a scientific basis for future therapeutic approaches to diseases of both the immune and skeletal systems.

Keywords

Bone destruction osteoclast RANKL TH17 NFATc1 

References

  1. 1.
    Takayanagi H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol. 2007;7:292–304.PubMedCrossRefGoogle Scholar
  2. 2.
    Theill LE, Boyle WJ, Penninger JM. RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu Rev Immunol. 2002;20:795–823.PubMedCrossRefGoogle Scholar
  3. 3.
    Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell. 2002;2:389–406.PubMedCrossRefGoogle Scholar
  4. 4.
    Walsh MC, Kim N, Kadono Y, Rho J, Lee SY, Lorenzo J, et al. Osteoimmunology: interplay between the immune system and bone metabolism. Annu Rev Immunol. 2006;24:33–63.PubMedCrossRefGoogle Scholar
  5. 5.
    Horton JE, Raisz LG, Simmons HA, Oppenheim JJ, Mergenhagen SE. Bone resorbing activity in supernatant fluid from cultured human peripheral blood leukocytes. Science. 1972;177:793–795.PubMedCrossRefGoogle Scholar
  6. 6.
    Gowen M, Wood DD, Ihrie EJ, McGuire MK, Russell RG. An interleukin 1 like factor stimulates bone resorption in vitro. Nature. 1983;306:378–380.PubMedCrossRefGoogle Scholar
  7. 7.
    Dewhirst FE, Stashenko PP, Mole JE, Tsurumachi T. Purification and partial sequence of human osteoclast-activating factor: identity with interleukin 1 β. J Immunol. 1985;135:2562–2568.PubMedGoogle Scholar
  8. 8.
    Takahashi N, Akatsu T, Udagawa N, Sasaki T, Yamaguchi A, Moseley JM, et al. Osteoblastic cells are involved in osteoclast formation. Endocrinology. 1988;123:2600–2602.PubMedCrossRefGoogle Scholar
  9. 9.
    Takahashi N, Yamana H, Yoshiki S, Roodman GD, Mundy GR, Jones SJ, et al. Osteoclast-like cell formation and its regulation by osteotropic hormones in mouse bone marrow cultures. Endocrinology. 1988;122:1373–1382.PubMedCrossRefGoogle Scholar
  10. 10.
    Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev. 1999;20:345–357.PubMedCrossRefGoogle Scholar
  11. 11.
    Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997;89:309–319.PubMedCrossRefGoogle Scholar
  12. 12.
    Yasuda H, Shima N, Nakagawa N, Mochizuki SI, Yano K, Fujise N, et al. Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology. 1998;139:1329–1337.PubMedCrossRefGoogle Scholar
  13. 13.
    Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93:165–176.PubMedCrossRefGoogle Scholar
  14. 14.
    Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A. 1998;95:3597–3602.PubMedCrossRefGoogle Scholar
  15. 15.
    Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 1997;390:175–179.PubMedCrossRefGoogle Scholar
  16. 16.
    Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, et al. 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. 1997;272:25190–25194.PubMedCrossRefGoogle Scholar
  17. 17.
    Tsuda E, Goto M, Mochizuki S, Yano K, Kobayashi F, Morinaga T, et al. Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem Biophys Res Commun. 1997;234:137–142.PubMedCrossRefGoogle Scholar
  18. 18.
    Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999;397:315–323.PubMedCrossRefGoogle Scholar
  19. 19.
    Kim N, Odgren PR, Kim DK, Marks SC Jr, Choi Y. Diverse roles of the tumor necrosis factor family member TRANCE in skeletal physiology revealed by TRANCE deficiency and partial rescue by a lymphocyte-expressed TRANCE transgene. Proc Natl Acad Sci U S A. 2000;97:10905–10910.PubMedCrossRefGoogle Scholar
  20. 20.
    Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T, et al. RANK is essential for osteoclast and lymph node development. Genes Dev. 1999;13:2412–2424.PubMedCrossRefGoogle Scholar
  21. 21.
    Li J, Sarosi I, Yan XQ, Morony S, Capparelli C, Tan HL, et al. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci U S A. 2000;97:1566–1571.PubMedCrossRefGoogle Scholar
  22. 22.
    Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, et al. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998;12:1260–1268.PubMedCrossRefGoogle Scholar
  23. 23.
    Mizuno A, Amizuka N, Irie K, Murakami A, Fujise N, Kanno T, et al. Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun. 1998;247:610–615.PubMedCrossRefGoogle Scholar
  24. 24.
    Sobacchi C, Frattini A, Guerrini MM, Abinun M, Pangrazio A, Susani L, et al. Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet. 2007;39:960–962.PubMedCrossRefGoogle Scholar
  25. 25.
    Hughes AE, Ralston SH, Marken J, Bell C, MacPherson H, Wallace RG, et al. Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet. 2000;24:45–48.PubMedCrossRefGoogle Scholar
  26. 26.
    Whyte MP, Obrecht SE, Finnegan PM, Jones JL, Podgornik MN, McAlister WH, et al. Osteoprotegerin deficiency and juvenile Paget’s disease. N Engl J Med. 2002;347:175–184.PubMedCrossRefGoogle Scholar
  27. 27.
    Guerrini MM, Sobacchi C, Cassani B, Abinun M, Kilic SS, Pangrazio A, et al. Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. Am J Hum Genet. 2008;83:64–76.PubMedCrossRefGoogle Scholar
  28. 28.
    Whyte MP. Paget’s disease of bone and genetic disorders of RANKL/OPG/RANK/NF-κB signaling. Ann N Y Acad Sci. 2006;1068:143–164.PubMedCrossRefGoogle Scholar
  29. 29.
    Nakashima T, Kobayashi Y, Yamasaki S, Kawakami A, Eguchi K, Sasaki H, et al. Protein expression and functional difference of membrane-bound and soluble receptor activator of NF-κB ligand: modulation of the expression by osteotropic factors and cytokines. Biochem Biophys Res Commun. 2000;275:768–775.PubMedCrossRefGoogle Scholar
  30. 30.
    Schlondorff J, Lum L, Blobel CP. Biochemical and pharmacological criteria define two shedding activities for TRANCE/OPGL that are distinct from the tumor necrosis factor alpha convertase. J Biol Chem. 2001;276:14665–14674.PubMedCrossRefGoogle Scholar
  31. 31.
    Miyamoto T, Arai F, Ohneda O, Takagi K, Anderson DM, Suda T. An adherent condition is required for formation of multinuclear osteoclasts in the presence of macrophage colony-stimulating factor and receptor activator of nuclear factor κB ligand. Blood. 2000;96:4335–4343.PubMedGoogle Scholar
  32. 32.
    Hikita A, Yana I, Wakeyama H, Nakamura M, Kadono Y, Oshima Y, et al. Negative regulation of osteoclastogenesis by ectodomain shedding of receptor activator of NF-κB ligand. J Biol Chem. 2006;281:36846–36855.PubMedCrossRefGoogle Scholar
  33. 33.
    Jones DH, Nakashima T, Sanchez OH, Kozieradzki I, Komarova SV, Sarosi I, et al. Regulation of cancer cell migration and bone metastasis by RANKL. Nature. 2006;440:692–696.PubMedCrossRefGoogle Scholar
  34. 34.
    Jimi E, Akiyama S, Tsurukai T, Okahashi N, Kobayashi K, Udagawa N, et al. Osteoclast differentiation factor acts as a multifunctional regulator in murine osteoclast differentiation and function. J Immunol. 1999;163:434–442.PubMedGoogle Scholar
  35. 35.
    Kim D, Mebius RE, MacMicking JD, Jung S, Cupedo T, Castellanos Y, et al. Regulation of peripheral lymph node genesis by the tumor necrosis factor family member TRANCE. J Exp Med. 2000;192:1467–1478.PubMedCrossRefGoogle Scholar
  36. 36.
    McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:821–831.PubMedCrossRefGoogle Scholar
  37. 37.
    Bachmann MF, Wong BR, Josien R, Steinman RM, Oxenius A, Choi Y. TRANCE, a tumor necrosis factor family member critical for CD40 ligand-independent T helper cell activation. J Exp Med. 1999;189:1025–1031.PubMedCrossRefGoogle Scholar
  38. 38.
    Moschen AR, Kaser A, Enrich B, Ludwiczek O, Gabriel M, Obrist P, et al. The RANKL/OPG system is activated in inflammatory bowel disease and relates to the state of bone loss. Gut. 2005;54:479–487.PubMedCrossRefGoogle Scholar
  39. 39.
    Ashcroft AJ, Cruickshank SM, Croucher PI, Perry MJ, Rollinson S, Lippitt JM, et al. Colonic dendritic cells, intestinal inflammation, and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin. Immunity. 2003;19:849–861.PubMedCrossRefGoogle Scholar
  40. 40.
    Loser K, Mehling A, Loeser S, Apelt J, Kuhn A, Grabbe S, et al. Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nat Med. 2006;12:1372–1379.PubMedCrossRefGoogle Scholar
  41. 41.
    Rossi SW, Kim MY, Leibbrandt A, Parnell SM, Jenkinson WE, Glanville SH, et al. RANK signals from CD4+3- inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J Exp Med. 2007;204:1267–1272.PubMedCrossRefGoogle Scholar
  42. 42.
    Akiyama T, Shimo Y, Yanai H, Qin J, Ohshima D, Maruyama Y, et al. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity. 2008;29:423–437.PubMedCrossRefGoogle Scholar
  43. 43.
    Hikosaka Y, Nitta T, Ohigashi I, Yano K, Ishimaru N, Hayashi Y, et al. The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity. 2008;29:438–450.PubMedCrossRefGoogle Scholar
  44. 44.
    Lomaga MA, Yeh WC, Sarosi I, Duncan GS, Furlonger C, Ho A, et al. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 1999;13:1015–1024.PubMedCrossRefGoogle Scholar
  45. 45.
    Naito A, Azuma S, Tanaka S, Miyazaki T, Takaki S, Takatsu K, et al. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells. 1999;4:353–362.PubMedCrossRefGoogle Scholar
  46. 46.
    Wong BR, Besser D, Kim N, Arron JR, Vologodskaia M, Hanafusa H, et al. TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol Cell. 1999;4:1041–1049.PubMedCrossRefGoogle Scholar
  47. 47.
    Kobayashi N, Kadono Y, Naito A, Matsumoto K, Yamamoto T, Tanaka S, et al. Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. EMBO J. 2001;20:1271–1280.PubMedCrossRefGoogle Scholar
  48. 48.
    Franzoso G, Carlson L, Xing L, Poljak L, Shores EW, Brown KD, et al. Requirement for NF-κB in osteoclast and B-cell development. Genes Dev. 1997;11:3482–3496.PubMedCrossRefGoogle Scholar
  49. 49.
    Iotsova V, Caamano J, Loy J, Yang Y, Lewin A, Bravo R. Osteopetrosis in mice lacking NF-κB1 and NF-κB2. Nat Med. 1997;3:1285–1289.PubMedCrossRefGoogle Scholar
  50. 50.
    Ruocco MG, Maeda S, Park JM, Lawrence T, Hsu LC, Cao Y, et al. IκB kinase (IKK)β, but not IKKα, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss. J Exp Med. 2005;201:1677–1687.PubMedCrossRefGoogle Scholar
  51. 51.
    Doffinger R, Smahi A, Bessia C, Geissmann F, Feinberg J, Durandy A, et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-κB signaling. Nat Genet. 2001;27:277–285.PubMedCrossRefGoogle Scholar
  52. 52.
    Gohda J, Akiyama T, Koga T, Takayanagi H, Tanaka S, Inoue J. RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis. EMBO J. 2005;24:790–799.PubMedCrossRefGoogle Scholar
  53. 53.
    Wada T, Nakashima T, Oliveira-dos-Santos AJ, Gasser J, Hara H, Schett G, et al. The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis. Nat Med. 2005;11:394–399.PubMedCrossRefGoogle Scholar
  54. 54.
    Bai S, Kitaura H, Zhao H, Chen J, Muller JM, Schule R, et al. FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner. J Clin Invest. 2005;115:2742–2751.PubMedCrossRefGoogle Scholar
  55. 55.
    Jin W, Chang M, Paul EM, Babu G, Lee AJ, Reiley W, et al. Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice. J Clin Invest. 2008;118:1858–1866.PubMedCrossRefGoogle Scholar
  56. 56.
    Wagner EF, Eferl R. Fos/AP-1 proteins in bone and the immune system. Immunol Rev. 2005;208:126–140.PubMedCrossRefGoogle Scholar
  57. 57.
    Sato K, Suematsu A, Nakashima T, Takemoto-Kimura S, Aoki K, Morishita Y, et al. Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nat Med. 2006;12:1410–1416.PubMedCrossRefGoogle Scholar
  58. 58.
    Yamashita T, Yao Z, Li F, Zhang Q, Badell IR, Schwarz EM, et al. 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. 2007;282:18245–18253.PubMedCrossRefGoogle Scholar
  59. 59.
    Faccio R, Takeshita S, Zallone A, Ross FP, Teitelbaum SL. c-Fms and the αvβ3 integrin collaborate during osteoclast differentiation. J Clin Invest. 2003;111:749–758.PubMedGoogle Scholar
  60. 60.
    Wan Y, Chong LW, Evans RM. PPAR-γ regulates osteoclastogenesis in mice. Nat Med. 2007;13:1496–1503.PubMedCrossRefGoogle Scholar
  61. 61.
    Ishii KA, Fumoto T, Iwai K, Takeshita S, Ito M, Shimohata N, et al. Coordination of PGC-1β and iron uptake in mitochondrial biogenesis and osteoclast activation. Nat Med. 2009;15:259–266.PubMedCrossRefGoogle Scholar
  62. 62.
    Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling for terminal differentiation of osteoclasts. Dev Cell. 2002;3:889–901.PubMedCrossRefGoogle Scholar
  63. 63.
    Crabtree GR, Olson EN. NFAT signaling: choreographing the social lives of cells. Cell. 2002;109(Suppl):S67–79.PubMedCrossRefGoogle Scholar
  64. 64.
    Hogan PG, Chen L, Nardone J, Rao A. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 2003;17:2205–2232.PubMedCrossRefGoogle Scholar
  65. 65.
    Asagiri M, Sato K, Usami T, Ochi S, Nishina H, Yoshida H, et al. Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med. 2005;202:1261–1269.PubMedCrossRefGoogle Scholar
  66. 66.
    Winslow MM, Pan M, Starbuck M, Gallo EM, Deng L, Karsenty G, et al. Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev Cell. 2006;10:771–782.PubMedCrossRefGoogle Scholar
  67. 67.
    Aliprantis AO, Ueki Y, Sulyanto R, Park A, Sigrist KS, Sharma SM, et al. NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism. J Clin Invest. 2008;118:3775–3789.PubMedCrossRefGoogle Scholar
  68. 68.
    Matsuo K, Galson DL, Zhao C, Peng L, Laplace C, Wang KZ, et al. Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos. J Biol Chem. 2004;279:26475–26480.PubMedCrossRefGoogle Scholar
  69. 69.
    Lee SH, Rho J, Jeong D, Sul JY, Kim T, Kim N, et al. v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation. Nat Med. 2006;12:1403–1409.PubMedCrossRefGoogle Scholar
  70. 70.
    Yagi M, Miyamoto T, Sawatani Y, Iwamoto K, Hosogane N, Fujita N, et al. DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells. J Exp Med. 2005;202:345–351.PubMedCrossRefGoogle Scholar
  71. 71.
    Kim K, Lee SH, Ha Kim J, Choi Y, Kim N. NFATc1 induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP). Mol Endocrinol. 2008;22:176–185.PubMedCrossRefGoogle Scholar
  72. 72.
    Komarova SV, Pereverzev A, Shum JW, Sims SM, Dixon SJ. Convergent signaling by acidosis and receptor activator of NF-κB ligand (RANKL) on the calcium/calcineurin/NFAT pathway in osteoclasts. Proc Natl Acad Sci U S A. 2005;102:2643–2648.PubMedCrossRefGoogle Scholar
  73. 73.
    Koga T, Inui M, Inoue K, Kim S, Suematsu A, Kobayashi E, et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature. 2004;428:758–763.PubMedCrossRefGoogle Scholar
  74. 74.
    Zou W, Reeve JL, Liu Y, Teitelbaum SL, Ross FP. DAP12 couples c-Fms activation to the osteoclast cytoskeleton by recruitment of Syk. Mol Cell. 2008;31:422–431.PubMedCrossRefGoogle Scholar
  75. 75.
    Mocsai A, Humphrey MB, Van Ziffle JA, Hu Y, Burghardt A, Spusta SC, et al. 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 U S A. 2004;101:6158–6163.PubMedCrossRefGoogle Scholar
  76. 76.
    Shinohara M, Koga T, Okamoto K, Sakaguchi S, Arai K, Yasuda H, et al. Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell. 2008;132:794–806.PubMedCrossRefGoogle Scholar
  77. 77.
    Yang S, Li YP. RGS10-null mutation impairs osteoclast differentiation resulting from the loss of [Ca2+]i oscillation regulation. Genes Dev. 2007;21:1803–1816.PubMedCrossRefGoogle Scholar
  78. 78.
    Masuyama R, Vriens J, Voets T, Karashima Y, Owsianik G, Vennekens R, et al. TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts. Cell Metab. 2008;8:257–265.PubMedCrossRefGoogle Scholar
  79. 79.
    Kuroda Y, Hisatsune C, Nakamura T, Matsuo K, Mikoshiba K. Osteoblasts induce Ca2+ oscillation-independent NFATc1 activation during osteoclastogenesis. Proc Natl Acad Sci U S A. 2008;105:8643–8648.PubMedCrossRefGoogle Scholar
  80. 80.
    Tomida T, Hirose K, Takizawa A, Shibasaki F, Iino M. NFAT functions as a working memory of Ca2+ signals in decoding Ca2+ oscillation. EMBO J. 2003;22:3825–3832.PubMedCrossRefGoogle Scholar
  81. 81.
    Mao D, Epple H, Uthgenannt B, Novack DV, Faccio R. PLCgamma2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2. J Clin Invest. 2006;116:2869–2879.PubMedCrossRefGoogle Scholar
  82. 82.
    Bromley M, Woolley DE. Chondroclasts and osteoclasts at subchondral sites of erosion in the rheumatoid joint. Arthritis Rheum. 1984;27:968–975.PubMedCrossRefGoogle Scholar
  83. 83.
    Gravallese EM, Harada Y, Wang JT, Gorn AH, Thornhill TS, Goldring SR. Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis. Am J Pathol. 1998;152:943–951.PubMedGoogle Scholar
  84. 84.
    Takayanagi H, Oda H, Yamamoto S, Kawaguchi H, Tanaka S, Nishikawa T, et al. A new mechanism of bone destruction in rheumatoid arthritis: synovial fibroblasts induce osteoclastogenesis. Biochem Biophys Res Commun. 1997;240:279–286.PubMedCrossRefGoogle Scholar
  85. 85.
    Takayanagi H, Iizuka H, Juji T, Nakagawa T, Yamamoto A, Miyazaki T, et al. Involvement of receptor activator of nuclear factor κB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum. 2000;43:259–269.PubMedCrossRefGoogle Scholar
  86. 86.
    Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature. 1999;402:304–309.PubMedCrossRefGoogle Scholar
  87. 87.
    Gravallese EM, Manning C, Tsay A, Naito A, Pan C, Amento E, et al. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum. 2000;43:250–258.PubMedCrossRefGoogle Scholar
  88. 88.
    Pettit AR, Ji H, von Stechow D, Muller R, Goldring SR, Choi Y, et al. TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am J Pathol. 2001;159:1689–1699.PubMedGoogle Scholar
  89. 89.
    Redlich K, Hayer S, Ricci R, David JP, Tohidast-Akrad M, Kollias G, et al. Osteoclasts are essential for TNF-α-mediated joint destruction. J Clin Invest. 2002;110:1419–1427.PubMedGoogle Scholar
  90. 90.
    Takayanagi H, Juji T, Miyazaki T, Iizuka H, Takahashi T, Isshiki M, et al. Suppression of arthritic bone destruction by adenovirus-mediated csk gene transfer to synoviocytes and osteoclasts. J Clin Invest. 1999;104:137–146.PubMedCrossRefGoogle Scholar
  91. 91.
    Lubberts E, Joosten LA, Chabaud M, van Den Bersselaar L, Oppers B, Coenen-De Roo CJ, et al. IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion. J Clin Invest. 2000;105:1697–1710.PubMedCrossRefGoogle Scholar
  92. 92.
    Horwood NJ, Kartsogiannis V, Quinn JM, Romas E, Martin TJ, Gillespie MT. Activated T lymphocytes support osteoclast formation in vitro. Biochem Biophys Res Commun. 1999;265:144–150.PubMedCrossRefGoogle Scholar
  93. 93.
    Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, et al. T cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. Nature. 2000;408:600–605.PubMedCrossRefGoogle Scholar
  94. 94.
    Firestein GS, Zvaifler NJ. How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum. 1990;33:768–773.PubMedCrossRefGoogle Scholar
  95. 95.
    Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006;203:2673–2682.PubMedCrossRefGoogle Scholar
  96. 96.
    Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999;109:1345–1352.CrossRefGoogle Scholar
  97. 97.
    Bailey SL, Schreiner B, McMahon EJ, Miller SD. CNS myeloid DCs presenting endogenous myelin peptides ‘preferentially’ polarize CD4+ TH-17 cells in relapsing EAE. Nat Immunol. 2007;8:172–180.PubMedCrossRefGoogle Scholar
  98. 98.
    Ousman SS, Tomooka BH, van Noort JM, Wawrousek EF, O’Conner K, Hafler DA, et al. Protective and therapeutic role for αB-crystallin in autoimmune demyelination. Nature. 2007;448:474–479.PubMedCrossRefGoogle Scholar
  99. 99.
    van Beelen AJ, Zelinkova Z, Taanman-Kueter EW, Muller FJ, Hommes DW, Zaat SA, et al. Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells. Immunity. 2007;27:660–669.PubMedCrossRefGoogle Scholar
  100. 100.
    Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity. 2006;24:677–688.PubMedCrossRefGoogle Scholar
  101. 101.
    Iwakura Y, Ishigame H. The IL-23/IL-17 axis in inflammation. J Clin Invest. 2006;116:1218–1222.PubMedCrossRefGoogle Scholar
  102. 102.
    Frey O, Petrow PK, Gajda M, Siegmund K, Huehn J, Scheffold A, et al. The role of regulatory T cells in antigen-induced arthritis: aggravation of arthritis after depletion and amelioration after transfer of CD4+CD25+ T cells. Arthritis Res Ther. 2005;7:R291–301.PubMedCrossRefGoogle Scholar
  103. 103.
    Zaiss MM, Axmann R, Zwerina J, Polzer K, Guckel E, Skapenko A, et al. Treg cells suppress osteoclast formation: a new link between the immune system and bone. Arthritis Rheum. 2007;56:4104–4112.PubMedCrossRefGoogle Scholar
  104. 104.
    Palladino MA, Bahjat FR, Theodorakis EA, Moldawer LL. Anti-TNF-α therapies: the next generation. Nat Rev Drug Discov. 2003;2:736–746.PubMedCrossRefGoogle Scholar
  105. 105.
    Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med. 2007;13:156–163.PubMedCrossRefGoogle Scholar
  106. 106.
    Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor κB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev. 2008;29:155–192.PubMedCrossRefGoogle Scholar
  107. 107.
    Luo JL, Tan W, Ricono JM, Korchynskyi O, Zhang M, Gonias SL, et al. Nuclear cytokine-activated IKKα controls prostate cancer metastasis by repressing Maspin. Nature. 2007;446:690–694.PubMedCrossRefGoogle Scholar
  108. 108.
    Kim H, Choi HK, Shin JH, Kim KH, Huh JY, Lee SA, et al. Selective inhibition of RANK blocks osteoclast maturation and function and prevents bone loss in mice. J Clin Invest. 2009;119:813–825.PubMedCrossRefGoogle Scholar
  109. 109.
    Nishimoto N, Kishimoto T. Interleukin 6: from bench to bedside. Nat Clin Pract Rheumatol. 2006;2:619–626.PubMedCrossRefGoogle Scholar
  110. 110.
    Jimi E, Aoki K, Saito H, D’Acquisto F, May MJ, Nakamura I, et al. Selective inhibition of NF-κB blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo. Nat Med. 2004;10:617–624.PubMedCrossRefGoogle Scholar
  111. 111.
    Urushibara M, Takayanagi H, Koga T, Kim S, Isobe M, Morishita Y, et al. The antirheumatic drug leflunomide inhibits osteoclastogenesis by interfering with receptor activator of NF-κB ligand-stimulated induction of nuclear factor of activated T cells c1. Arthritis Rheum. 2004;50:794–804.PubMedCrossRefGoogle Scholar
  112. 112.
    Suematsu A, Tajiri Y, Nakashima T, Taka J, Ochi S, Oda H, et al. Scientific basis for the efficacy of combined use of antirheumatic drugs against bone destruction in rheumatoid arthritis. Mod Rheumatol. 2007;17:17–23.PubMedCrossRefGoogle Scholar
  113. 113.
    Kollet O, Dar A, Lapidot T. The multiple roles of osteoclasts in host defense: bone remodeling and hematopoietic stem cell mobilization. Annu Rev Immunol. 2007;25:51–69.PubMedCrossRefGoogle Scholar
  114. 114.
    Nagasawa T. Microenvironmental niches in the bone marrow required for B-cell development. Nat Rev Immunol. 2006;6:107–116.PubMedCrossRefGoogle Scholar
  115. 115.
    Kollet O, Dar A, Shivtiel S, Kalinkovich A, Lapid K, Sztainberg Y, et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med. 2006;12:657–664.PubMedCrossRefGoogle Scholar
  116. 116.
    Mizoguchi T, Muto A, Udagawa N, Arai A, Yamashita T, Hosoya A, et al. Identification of cell cycle-arrested quiescent osteoclast precursors in vivo. J Cell Biol. 2009;184:541–554.PubMedCrossRefGoogle Scholar
  117. 117.
    Ishii M, Egen JG, Klauschen F, Meier-Schellersheim M, Saeki Y, Vacher J, et al. Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. Nature. 2009;458:524–528.PubMedCrossRefGoogle Scholar
  118. 118.
    Asagiri M, Hirai T, Kunigami T, Kamano S, Gober HJ, Okamoto K, et al. Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis. Science. 2008;319:624–627.PubMedCrossRefGoogle Scholar
  119. 119.
    Fata JE, Kong YY, Li J, Sasaki T, Irie-Sasaki J, Moorehead RA, et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell. 2000;103:41–50.PubMedCrossRefGoogle Scholar
  120. 120.
    Mizuno A, Kanno T, Hoshi M, Shibata O, Yano K, Fujise N, et al. Transgenic mice overexpressing soluble osteoclast differentiation factor (sODF) exhibit severe osteoporosis. J Bone Miner Metab. 2002;20:337–344.PubMedCrossRefGoogle Scholar
  121. 121.
    Li P, Schwarz EM, O’Keefe RJ, Ma L, Boyce BF, Xing L. RANK signaling is not required for TNFα-mediated increase in CD11bhi osteoclast precursors but is essential for mature osteoclast formation in TNFα-mediated inflammatory arthritis. J Bone Miner Res. 2004;19:207–213.PubMedCrossRefGoogle Scholar
  122. 122.
    Gonzalez-Suarez E, Branstetter D, Armstrong A, Dinh H, Blumberg H, Dougall WC. RANK overexpression in transgenic mice with mouse mammary tumor virus promoter-controlled RANK increases proliferation and impairs alveolar differentiation in the mammary epithelia and disrupts lumen formation in cultured epithelial acini. Mol Cell Biol. 2007;27:1442–1454.PubMedCrossRefGoogle Scholar
  123. 123.
    Kanzaki S, Ito M, Takada Y, Ogawa K, Matsuo K. Resorption of auditory ossicles and hearing loss in mice lacking osteoprotegerin. Bone. 2006;39:414–419.PubMedCrossRefGoogle Scholar
  124. 124.
    Min H, Morony S, Sarosi I, Dunstan CR, Capparelli C, Scully S, et al. Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis. J Exp Med. 2000;192:463–474.PubMedCrossRefGoogle Scholar
  125. 125.
    Palenzuela L, Vives-Bauza C, Fernandez-Cadenas I, Meseguer A, Font N, Sarret E, et al. Familial expansile osteolysis in a large Spanish kindred resulting from an insertion mutation in the TNFRSF11A gene. J Med Genet. 2002;39:E67.PubMedCrossRefGoogle Scholar
  126. 126.
    Johnson-Pais TL, Singer FR, Bone HG, McMurray CT, Hansen MF, Leach RJ. Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis. J Bone Miner Res. 2003;18:376–380.PubMedCrossRefGoogle Scholar
  127. 127.
    Nakatsuka K, Nishizawa Y, Ralston SH. Phenotypic characterization of early onset Paget’s disease of bone caused by a 27-bp duplication in the TNFRSF11A gene. J Bone Miner Res. 2003;18:1381–1385.PubMedCrossRefGoogle Scholar
  128. 128.
    Whyte MP, Hughes AE. Expansile skeletal hyperphosphatasia is caused by a 15-base pair tandem duplication in TNFRSF11A encoding RANK and is allelic to familial expansile osteolysis. J Bone Miner Res. 2002;17:26–29.PubMedCrossRefGoogle Scholar
  129. 129.
    Cundy T, Hegde M, Naot D, Chong B, King A, Wallace R, et al. A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype. Hum Mol Genet. 2002;11:2119–2127.PubMedCrossRefGoogle Scholar
  130. 130.
    Chong B, Hegde M, Fawkner M, Simonet S, Cassinelli H, Coker M, et al. Idiopathic hyperphosphatasia and TNFRSF11B mutations: relationships between phenotype and genotype. J Bone Miner Res. 2003;18:2095–2104.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Cell Signaling, Graduate School of Medical and Dental ScienceTokyo Medical and Dental UniversityTokyoJapan
  2. 2.Global Center of Excellence (GCOE) ProgramInternational Research Center for Molecular Science in Tooth and Bone DiseasesTokyoJapan

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