Journal of Molecular Medicine

, Volume 83, Issue 3, pp 170–179 | Cite as

Mechanistic insight into osteoclast differentiation in osteoimmunology

Review

Abstract

Recently a close relationship between the immune and skeletal systems or the interdisciplinary field called osteoimmunology has attracted much attention due to the observations that bone destruction is caused by an abnormal activation of the immune system in rheumatoid arthritis, and that mice lacking immunomodulatory molecules often exhibit an unexpected bone phenotype. Osteoclasts are cells of monocyte/macrophage origin that degrade the bone matrix. They are among the key players in the control of bone metabolism in health and disease. Receptor activator of NF-κB ligand (RANKL), a tumor necrosis factor (TNF) family cytokine, induces the differentiation of osteoclasts in the presence of macrophage-colony stimulating factor. RANKL activates TRAF6, c-Fos, and calcium signaling pathways, all of which are indispensable for the induction and activation of nuclear factor of activated T cells (NFAT) c1, the master transcription factor for osteoclastogenesis. The autoamplification of NFATc1 gene results in the efficient induction of osteoclast-specific genes. An AP-1 transcription factor complex containing c-Fos plays a crucial role in these processes, although results in conditional knockout mice show that Jun family members have a redundant role. The immunoreceptor tyrosine-based activation motif (ITAM) is an important signaling component for a number of receptors in the immune system including T-cell, B-cell, NK-cell, and Fc receptors, but its contribution to the skeletal system remains unclarified. In search for the calcium-mobilizing mechanism during osteoclastogenesis we determined that multiple immunoglobulinlike receptors associated with ITAM-harboring adaptors, Fc receptor common γ chain (FcRγ), and DNAX-activating protein (DAP) 12, are essential for osteoclastogenesis. In osteoclast precursor cells FcRγ-associated receptors include osteoclast-associated receptor and paired immunoglobulinlike receptor A, while triggering receptor expressed in myeloid cells 2 and signal-regulatory protein β1 preferentially associate with DAP12. In cooperation with RANKL these receptors activate phospholipase Cγ and calcium signaling essential for the induction of NFATc1 through ITAM phosphorylation. Thus we have established the importance of the ITAM-mediated costimulatory signals in RANKL-induced osteoclast differentiation, which is analogous to the role of costimulatory signals in the immune system. Here we summarize recent advances in the study of signaling mechanism of osteoclast differentiation in the context of osteoimmunology.

Keywords

Bone Cell biology Cytokines Immunology Knockout 

Abbreviations

AP

Activator protein

BMM

Bone marrow-derived monocyte/macrophage precursor cell

DAP

DNAX-activating protein

FcRγ

Fc receptor common γ chain

IFN

Interferon

ITAM

Immunoreceptor tyrosine-based activation motif

JNK

Jun N-terminal kinase

MAPK

Mitogen-activated protein kinase

M-CSF

Macrophage-colony stimulating factor

MITF

Microphthalmia transcription factor

NF

Nuclear factor

NFAT

Nuclear factor of activated T cell

OPG

Osteoprotegerin

OSCAR

Osteoclast-associated receptor

RANK

Receptor activator of nuclear factor κB

RANKL

Receptor activator of nuclear factor κB ligand

TNF

Tumor necrosis factor

TRAF

TNF receptor-associated factor

TREM

Triggering receptor expressed in myeloid cells

Notes

Acknowledgements

I appreciate T. Taniguchi, T. Takai, M. Inui, T. Koga and S. Kim for their great contribution to the publications, on which this work is based. I also thank K. Matsuo, T. Nakajima, A. Suematsu, K. Sato, M. Asagiri and Y. Kim for critical reading of the manuscript and discussion. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and JSPS, the PRESTO program of JST, grants for the 21st century COE program, Health Sciences Research Grants from the Ministry of Health, Labor and Welfare of Japan, and grants from the Mitsubishi Foundation, The Kato Trust for Nambyo Research and Takeda Science foundation.

References

  1. 1.
    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 43:259–269CrossRefPubMedGoogle Scholar
  2. 2.
    Karsenty G, Wagner EF (2002) Reaching a genetic and molecular understanding of skeletal development. Dev Cell 2:389–406CrossRefPubMedGoogle Scholar
  3. 3.
    Teitelbaum SL, Ross FP (2003) Genetic regulation of osteoclast development and function. Nat Rev Genet 4:638–649Google Scholar
  4. 4.
    Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 95:3597–3602Google Scholar
  5. 5.
    Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176CrossRefPubMedGoogle Scholar
  6. 6.
    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 390:175–179CrossRefPubMedGoogle Scholar
  7. 7.
    Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett FSr, Frankel WN, Lee SY, Choi Y (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 272:25190–25194CrossRefPubMedGoogle Scholar
  8. 8.
    Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397:315–323CrossRefPubMedGoogle Scholar
  9. 9.
    Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, Akinori T, Yokochi T, Oda H, Tanaka K, Nakamura K, Taniguchi T (2000) T cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. Nature 408:600–605CrossRefPubMedGoogle Scholar
  10. 10.
    Arron JR, Choi Y (2000) Bone versus immune system. Nature 408:535–536CrossRefPubMedGoogle Scholar
  11. 11.
    Kim N, Takami M, Rho J, Josien R, Choi Y (2002) A novel member of the leukocyte receptor complex regulates osteoclast differentiation. J Exp Med 195:201–209PubMedGoogle Scholar
  12. 12.
    Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, Capparelli C, Li J, Elliott R, McCabe S, Wong T, Campagnuolo G, Moran E, Bogoch ER, Van G, Nguyen LT, Ohashi PS, Lacey DL, Fish E, Boyle WJ, Penninger JM (1999) Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402:304–309CrossRefPubMedGoogle Scholar
  13. 13.
    Lomaga MA, Yeh WC, Sarosi I, Duncan GS, Furlonger C, Ho A, Morony S, Capparelli C, Van G, Kaufman S, van der Heiden A, Itie A, Wakeham A, Khoo W, Sasaki T, Cao Z, Penninger JM, Paige CJ, Lacey DL, Dunstan CR, Boyle WJ, Goeddel DV, Mak TW (1999) TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev 13:1015–1024PubMedGoogle Scholar
  14. 14.
    Theill LE, Boyle WJ, Penninger JM (2002) RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu Rev Immunol 20:795–823CrossRefPubMedGoogle Scholar
  15. 15.
    Takayanagi H, Kim S, Matsuo K, Suzuki H, Suzuki T, Sato K, Yokochi T, Oda H, Nakamura K, Ida N, Wagner EF, Taniguchi T (2002) RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-β. Nature 416:744–749CrossRefPubMedGoogle Scholar
  16. 16.
    Kim S, Koga T, Isobe M, Kern BE, Yokochi T, Chin YE, Karsenty G, Taniguchi T, Takayanagi H (2003) Stat1 functions as a cytoplasmic atttenuator of Runx2 in the transcriptional program of osteoblast differentiation. Genes Dev 17:1979–1991CrossRefPubMedGoogle Scholar
  17. 17.
    Feldmann M, Maini RN (2001) Anti-TNF α therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 19:163–196CrossRefPubMedGoogle Scholar
  18. 18.
    Alliston T, Derynck R (2002) Interfering with bone remodelling. Nature 416:686–687CrossRefPubMedGoogle Scholar
  19. 19.
    Baron R (2004) Arming the osteoclast. Nat Med 10:458–460Google Scholar
  20. 20.
    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 20:345–357CrossRefPubMedGoogle Scholar
  21. 21.
    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 123:2600–2602PubMedGoogle Scholar
  22. 22.
    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 345:442–444CrossRefPubMedGoogle Scholar
  23. 23.
    Lagasse E, Weissman IL (1997) Enforced expression of Bcl-2 in monocytes rescues macrophages and partially reverses osteopetrosis in op/op mice. Cell 89:1021–1031CrossRefPubMedGoogle Scholar
  24. 24.
    Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342CrossRefPubMedGoogle Scholar
  25. 25.
    Koga T, Inui M, Inoue K, Kim S, Suematsu A, Kobayashi E, Iwata T, Ohnishi H, Matozaki T, Kodama T, Taniguchi T, Takayanagi H, Takai T (2004) Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428:758–763CrossRefPubMedGoogle Scholar
  26. 26.
    Wong BR, Josien R, Lee SY, Vologodskaia M, Steinman RM, Choi Y (1998) The TRAF family of signal transducers mediates NF-κB activation by the TRANCE receptor. J Biol Chem 273:28355–28359CrossRefPubMedGoogle Scholar
  27. 27.
    Naito A, Azuma S, Tanaka S, Miyazaki T, Takaki S, Takatsu K, Nakao K, Nakamura K, Katsuki M, Yamamoto T, Inoue J (1999) Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 4:353–362CrossRefPubMedGoogle Scholar
  28. 28.
    Kobayashi N, Kadono Y, Naito A, Matsumoto K, Yamamoto T, Tanaka S, Inoue J (2001) Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. EMBO J 20:1271–1280CrossRefPubMedGoogle Scholar
  29. 29.
    Matsuo K, Owens JM, Tonko M, Elliott C, Chambers TJ, Wagner EF (2000) Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation. Nat Genet 24:184–187Google Scholar
  30. 30.
    Wagner EF, Karsenty G (2001) Genetic control of skeletal development. Curr Opin Genet Dev 11:527–532CrossRefPubMedGoogle Scholar
  31. 31.
    Bohmann D, Bos TJ, Admon A, Nishimura T, Vogt PK, Tjian R (1987) Human proto-oncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1. Science 238:1386–1392PubMedGoogle Scholar
  32. 32.
    Franza BR Jr, Rauscher FJ, 3rd, Josephs SF, Curran T (1988) The Fos complex and Fos-related antigens recognize sequence elements that contain AP-1 binding sites. Science 239:1150–1153PubMedGoogle Scholar
  33. 33.
    Hai TW, Liu F, Allegretto EA, Karin M, Green MR (1988) A family of immunologically related transcription factors that includes multiple forms of ATF and AP-1. Genes Dev 2:1216–1226PubMedGoogle Scholar
  34. 34.
    Franzoso G, Carlson L, Xing L, Poljak L, Shores EW, Brown KD, Leonardi A, Tran T, Boyce BF, Siebenlist U (1997) Requirement for NF-κB in osteoclast and B-cell development. Genes Dev 11:3482–3496PubMedGoogle Scholar
  35. 35.
    Grigoriadis AE, Wang ZQ, Cecchini MG, Hofstetter W, Felix R, Fleisch HA, Wagner EF (1994) c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science 266:443–448PubMedGoogle Scholar
  36. 36.
    Fleischmann A, Hafezi F, Elliott C, Reme CE, Ruther U, Wagner EF (2000) Fra-1 replaces c-Fos-dependent functions in mice. Genes Dev 14:2695–2700CrossRefPubMedGoogle Scholar
  37. 37.
    David JP, Sabapathy K, Hoffmann O, Idarraga MH, Wagner EF (2002) JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and -independent mechanisms. J Cell Sci 115:4317–4325CrossRefPubMedGoogle Scholar
  38. 38.
    Kenner L, Hoebertz A, Beil T, Keon N, Karreth F, Eferl R, Scheuch H, Szremska A, Amling M, Schorpp-Kistner M, Angel P, Wagner EF (2004) Mice lacking JunB are osteopenic due to cell-autonomous osteoblast and osteoclast defects. J Cell Biol 164:613–623CrossRefPubMedGoogle Scholar
  39. 39.
    Ikeda F, Nishimura R, Matsubara T, Tanaka S, Inoue J, Reddy SV, Hata K, Yamashita K, Hiraga T, Watanabe T, Kukita T, Yoshioka K, Rao A, Yoneda T (2004) Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation. J Clin Invest 114:475–484CrossRefPubMedGoogle Scholar
  40. 40.
    Brown PH, Alani R, Preis LH, Szabo E, Birrer MJ (1993) Suppression of oncogene-induced transformation by a deletion mutant of c-jun. Oncogene 8:877–886PubMedGoogle Scholar
  41. 41.
    Brown PH, Chen TK, Birrer MJ (1994) Mechanism of action of a dominant-negative mutant of c-Jun. Oncogene 9:791–799PubMedGoogle Scholar
  42. 42.
    Dong Z, Xu RH, Kim J, Zhan SN, Ma WY, Colburn NH, Kung H (1996) AP-1/jun is required for early Xenopus development and mediates mesoderm induction by fibroblast growth factor but not by activin. J Biol Chem 271:9942–9946CrossRefPubMedGoogle Scholar
  43. 43.
    Tondravi MM, McKercher SR, Anderson K, Erdmann JM, Quiroz M, Maki R, Teitelbaum SL (1997) Osteopetrosis in mice lacking haematopoietic transcription factor PU.1. Nature 386:81–84CrossRefPubMedGoogle Scholar
  44. 44.
    Weilbaecher KN, Motyckova G, Huber WE, Takemoto CM, Hemesath TJ, Xu Y, Hershey CL, Dowland NR, Wells AG, Fisher DE (2001) Linkage of M-CSF signaling to Mitf, TFE3, and the osteoclast defect in Mitfmi/mi mice. Mol Cell 8:749–758CrossRefPubMedGoogle Scholar
  45. 45.
    McGill GG, Horstmann M, Widlund HR, Du J, Motyckova G, Nishimura EK, Lin YL, Ramaswamy S, Avery W, Ding HF, Jordan SA, Jackson IJ, Korsmeyer SJ, Golub TR, Fisher DE (2002) Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell 109:707–718CrossRefPubMedGoogle Scholar
  46. 46.
    So H, Rho J, Jeong D, Park R, Fisher DE, Ostrowski MC, Choi Y, Kim N (2003) Microphthalmia transcription factor and PU.1 synergistically induce the leukocyte receptor osteoclast-associated receptor gene expression. J Biol Chem 278:24209–24216CrossRefPubMedGoogle Scholar
  47. 47.
    Matsumoto M, Kogawa M, Wada S, Takayanagi H, Tsujimoto M, Katayama S, Hisatake K, Nogi Y (2004) Essential role of p38 MAP kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATc1 and PU.1. J Biol Chem 279:969–979CrossRefGoogle Scholar
  48. 48.
    Shirakawa F, Chedid M, Suttles J, Pollok BA, Mizel SB (1989) Interleukin 1 and cyclic AMP induce κ immunoglobulin light-chain expression via activation of an NF-κB-like DNA-binding protein. Mol Cell Biol 9:959–964PubMedGoogle Scholar
  49. 49.
    Muegge K, Williams TM, Kant J, Karin M, Chiu R, Schmidt A, Siebenlist U, Young HA, Durum SK (1989) Interleukin-1 costimulatory activity on the interleukin-2 promoter via AP-1. Science 246:249–251PubMedGoogle Scholar
  50. 50.
    Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K (1999) The kinase TAK1 can activate the NIK-I κB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature 398:252–256CrossRefPubMedGoogle Scholar
  51. 51.
    Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M, Yokochi T, Inoue J, Wagner EF, Mak TW, Kodama T, Taniguchi T (2002) Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling for terminal differentiation of osteoclasts. Dev Cell 3:889–901CrossRefPubMedGoogle Scholar
  52. 52.
    Rao A, Luo C, Hogan PG (1997) Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 15:707–747CrossRefPubMedGoogle Scholar
  53. 53.
    Shaw JP, Utz PJ, Durand DB, Toole JJ, Emmel EA, Crabtree GR (1988) Identification of a putative regulator of early T cell activation genes. Science 241:202–205PubMedGoogle Scholar
  54. 54.
    Berridge MJ, Lipp P, Bootman MD (2000) The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1:11–21Google Scholar
  55. 55.
    Crabtree GR, Olson EN (2002) NFAT signaling: choreographing the social lives of cells. Cell 109 [Suppl]:S67–S79Google Scholar
  56. 56.
    Ishida N, Hayashi K, Hoshijima M, Ogawa T, Koga S, Miyatake Y, Kumegawa M, Kimura T, Takeya T (2002) Large scale gene expression analysis of osteoclastogenesis in vitro and elucidation of NFAT2 as a key regulator. J Biol Chem 277:41147–41156CrossRefPubMedGoogle Scholar
  57. 57.
    Matsuo K, Galson DL, Zhao C, Peng L, Laplace C, Wang KZ, Bachler MA, Amano H, Aburatani H, Ishikawa H, Wagner EF (2004) Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos. J Biol Chem 279:26475–26480CrossRefPubMedGoogle Scholar
  58. 58.
    Munaut C, Salonurmi T, Kontusaari S, Reponen P, Morita T, Foidart JM, Tryggvason K (1999) Murine matrix metalloproteinase 9 gene. 5’-upstream region contains cis-acting elements for expression in osteoclasts and migrating keratinocytes in transgenic mice. J Biol Chem 274:5588–5596CrossRefPubMedGoogle Scholar
  59. 59.
    Kaifu T, Nakahara J, Inui M, Mishima K, Momiyama T, Kaji M, Sugahara A, Koito H, Ujike-Asai A, Nakamura A, Kanazawa K, Tan-Takeuchi K, Iwasaki K, Yokoyama WM, Kudo A, Fujiwara M, Asou H, Takai T (2003) Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J Clin Invest 111:323–332CrossRefPubMedGoogle Scholar
  60. 60.
    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 101:6158–6163CrossRefGoogle Scholar
  61. 61.
    Cerwenka A, Lanier LL (2001) Natural killer cells, viruses and cancer. Nat Rev Immunol 1:41–49CrossRefPubMedGoogle Scholar
  62. 62.
    Takai T (2002) Roles of Fc receptors in autoimmunity. Nat Rev Immunol 2:580–592Google Scholar
  63. 63.
    Faccio R, Zou W, Colaianni G, Teitelbaum SL, Ross FP (2003) High dose M-CSF partially rescues the Dap12-/- osteoclast phenotype. J Cell Biochem 90:871–883CrossRefPubMedGoogle Scholar
  64. 64.
    Aoki K, Didomenico E, Sims NA, Mukhopadhyay K, Neff L, Houghton A, Amling M, Levy JB, Horne WC, Baron R (1999) The tyrosine phosphatase SHP-1 is a negative regulator of osteoclastogenesis and osteoclast resorbing activity: increased resorption and osteopenia in mev/mev mutant mice. Bone 25:261–267CrossRefPubMedGoogle Scholar
  65. 65.
    Takeshita S, Namba N, Zhao JJ, Jiang Y, Genant HK, Silva MJ, Brodt MD, Helgason CD, Kalesnikoff J, Rauh MJ, Humphries RK, Krystal G, Teitelbaum SL, Ross FP (2002) SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclasts. Nat Med 8:943–949Google Scholar
  66. 66.
    Hayashi S, Tsuneto M, Yamada T, Nose M, Yoshino M, Shultz LD, Yamazaki H (2004) Lipopolysaccharide-induced osteoclastogenesis in Src homology 2-domain phosphatase-1-deficient viable motheaten mice. Endocrinology 145:2721–2729CrossRefPubMedGoogle Scholar
  67. 67.
    Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R, Bianchin M, Bird T, Miranda R, Salmaggi A, Tranebjaerg L, Konttinen Y, Peltonen L (2002) Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet 71:656–662CrossRefPubMedGoogle Scholar
  68. 68.
    Paloneva J, Mandelin J, Kiialainen A, Bohling T, Prudlo J, Hakola P, Haltia M, Konttinen YT, Peltonen L (2003) DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features. J Exp Med 198:669–675CrossRefPubMedGoogle Scholar
  69. 69.
    Cella M, Buonsanti C, Strader C, Kondo T, Salmaggi A, Colonna M (2003) Impaired differentiation of osteoclasts in TREM-2-deficient individuals. J Exp Med 198:645–651CrossRefPubMedGoogle Scholar
  70. 70.
    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 347:175–184CrossRefPubMedGoogle Scholar
  71. 71.
    Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS (1998) osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12:1260–1268PubMedGoogle Scholar
  72. 72.
    Hughes AE, Ralston SH, Marken J, Bell C, MacPherson H, Wallace RG, van Hul W, Whyte MP, Nakatsuka K, Hovy L, Anderson DM (2000) Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet 24:45–48CrossRefPubMedGoogle Scholar
  73. 73.
    Whyte MP, Hughes AE (2002) 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 17:26–29PubMedGoogle Scholar
  74. 74.
    Bekker PJ, Holloway DL, Rasmussen AS, Murphy R, Martin SW, Leese PT, Holmes GB, Dunstan CR, DePaoli AM (2004) A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res 19:1059–1066PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  1. 1.Department of Cellular Physiological Chemistry, COE Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Graduate SchoolTokyo Medical and Dental UniversityTokyoJapan
  2. 2.PRESTOJapan Science and Technology AgencySaitamaJapan

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