The Enigmatic Function of TREM-2 in Osteoclastogenesis

  • Marco Colonna
  • Isaiah Turnbull
  • Julia Klesney-Tait
Part of the Advances in Experimental Medicine and Biology book series (volume 602)

The triggering receptor expressed on myeloid cells 2 (TREM-2) is a member of family of receptors that play a central role in regulating function of myeloid cells. TREM-2 is expressed on macrophages, microglia and pre-osteoclasts and transduces intracellular signals through the adaptor DAP12. In human, genetic defects of TREM-2 and DAP12 result in a rare syndrome characterized by presenile dementia and bone cysts. This syndrome and the tissue distribution of TREM-2 have indicated a role of the TREM-2/DAP12 complex in brain function and bone modeling, particularly osteoclastogenesis. Accordingly, human TREM-2- and DAP12-deficient pre-osteoclast precursors failed to differentiate in vitro into mature osteoclasts endowed with bone resorptive activity. In mouse, DAP12-deficiency also resulted in impaired osteoclastogenesis in vitro and a mild osteopetrosis in vivo although bone cysts were not observed. Surprisingly, TREM-2-deficiency in mouse led to accelerated osteoclastogenesis in vitro without osteopetrosis or bone cysts in vivo, revealing an unexpected inhibitory function of mouse TREM-2. These data demonstrate that TREM-2 function is essential for normal osteoclastogenesis. The conflicting results as to the relationship between TREM-2, DAP12 and osteoclastogenesis and bone modeling in human and mouse suggest that TREM-2 contribution to osteoclast biology may vary depending on the influence of additional DAP12-associated receptors and on the presence of TREM-2 ligands with variable avidity/affinity, which may induce either activating or an inhibitory signals through TREM-2/DAP12.


Bone Cyst Bone Modeling Presenile Dementia DAP12 Signaling Adapter Protein DAP12 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aguilar, H., D. Alvarez-Errico, A.C. Garcia-Montero, A. Orfao, J. Sayos, and M. Lopez-Botet. 2004. Molecular characterization of a novel immune receptor restricted to the monocytic lineage. J Immunol 173: 6703–6711.PubMedGoogle Scholar
  2. Allcock, R.J., A.D. Barrow, S. Forbes, S. Beck, and J. Trowsdale. 2003. The human TREM gene cluster at 6p21.1 encodes both activating and inhibitory single IgV domain receptors and includes NKp44. Eur J Immunol 33: 567–577.CrossRefPubMedGoogle Scholar
  3. Asagiri, M., K. Sato, T. Usami, S. Ochi, H. Nishina, H. Yoshida, I. Morita, E.F. Wagner, T.W. Mak, E. Serfling, and H. Takayanagi. 2005. Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med 202: 1261–1269.CrossRefPubMedGoogle Scholar
  4. Bianchin, M.M., H.M. Capella, D.L. Chaves, M. Steindel, E.C. Grisard, G.G. Ganev, J.P. da Silva Junior, S. Neto Evaldo, M.A. Poffo, R. Walz, et al. 2004. Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy–PLOSL): a dementia associated with bone cystic lesions. From clinical to genetic and molecular aspects. Cell Mol Neurobiol 24: 1–24.CrossRefPubMedGoogle Scholar
  5. Bouchon, A., C. Hernandez-Munain, M. Cella, and M. Colonna. 2001. A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J Exp Med 194: 1111–1122.CrossRefPubMedGoogle Scholar
  6. Cantoni, C., C. Bottino, M. Vitale, A. Pessino, R. Augugliaro, A. Malaspina, S. Parolini, L. Moretta, A. Moretta, and R. Biassoni. 1999. NKp44, a triggering receptor involved in tumor cell lysis by activated human natural killer cells, is a novel member of the immunoglobulin superfamily. J Exp Med 189: 787–796.CrossRefPubMedGoogle Scholar
  7. Cella, M., C. Buonsanti, C. Strader, T. Kondo, A. Salmaggi, and M. Colonna. 2003. Impaired differentiation of osteoclasts in TREM-2-deficient individuals. J Exp Med 198: 645–651.CrossRefPubMedGoogle Scholar
  8. Chung, D.H., M.B. Humphrey, M.C. Nakamura, D.G. Ginzinger, W.E. Seaman, and M.R. Daws. 2003. CMRF-35-like molecule-1, a novel mouse myeloid receptor, can inhibit osteoclast formation. J Immunol 171: 6541–6548.PubMedGoogle Scholar
  9. Daws, M.R., L.L. Lanier, W.E. Seaman, and J.C. Ryan. 2001. Cloning and characterization of a novel mouse myeloid DAP12-associated receptor family. Eur J Immunol 31: 783–791.CrossRefPubMedGoogle Scholar
  10. Daws, M.R., P.M. Sullam, E.C. Niemi, T.T. Chen, N.K. Tchao, and W.E. Seaman. 2003. Pattern recognition by TREM-2: binding of anionic ligands. J Immunol 171: 594–599.PubMedGoogle Scholar
  11. Faccio, R., W. Zou, G. Colaianni, S.L. Teitelbaum, and F.P. Ross. 2003. High dose M-CSF partially rescues the Dap12−/− osteoclast phenotype. J Cell Biochem 90: 871–883.CrossRefPubMedGoogle Scholar
  12. Hakola, H.P., O.H. Jarvi, and P. Sourander. 1970. Osteodysplasia polycystica hereditaria combined with sclerosing leucoencephalopathy, a new entity of the dementia praesenilis group. Acta Neurol Scand 46(Suppl): 79+.CrossRefPubMedGoogle Scholar
  13. Hamerman, J.A., J.R. Jarjoura, M.B. Humphrey, M.C. Nakamura, W.E. Seaman, and L.L. Lanier. 2006. Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12. J Immunol 177: 2051–2055.PubMedGoogle Scholar
  14. Hamerman, J.A., and L.L. Lanier. 2006. Inhibition of immune responses by ITAM-bearing receptors. Sci STKE 2006: re1.Google Scholar
  15. Hamerman, J.A., N.K. Tchao, C.A. Lowell, and L.L. Lanier. 2005. Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12. Nat Immunol 6: 579–586.CrossRefPubMedGoogle Scholar
  16. Humphrey, M.B., M.R. Daws, S.C. Spusta, E.C. Niemi, J.A. Torchia, L.L. Lanier, W.E. Seaman, and M.C. Nakamura 2006. TREM2, a DAP12-associated receptor, regulates osteoclast differentiation and function. J Bone Miner Res 21: 237–245.CrossRefPubMedGoogle Scholar
  17. Humphrey, M.B., L.L. Lanier, and M.C. Nakamura. 2005. Role of ITAM-containing adapter proteins and their receptors in the immune system and bone. Immunol Rev 208: 50–65.CrossRefPubMedGoogle Scholar
  18. Humphrey, M.B., K. Ogasawara, W. Yao, S.C. Spusta, M.R. Daws, N.E. Lane, L.L. Lanier, and M.C. Nakamura. 2004. The signaling adapter protein DAP12 regulates multinucleation during osteoclast development. J Bone Miner Res 19: 224–234.CrossRefPubMedGoogle Scholar
  19. Jackson, D.G., D.N. Hart, G. Starling, and J.I. Bell. 1992. Molecular cloning of a novel member of the immunoglobulin gene superfamily homologous to the polymeric immunoglobulin receptor. Eur J Immunol 22: 1157–1163.CrossRefPubMedGoogle Scholar
  20. Kaifu, T., J. Nakahara, M. Inui, K. Mishima, T. Momiyama, M. Kaji, A. Sugahara, H. Koito, A. Ujike-Asai, A. Nakamura, et al. 2003. Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J Clin Invest 111: 323–332.PubMedGoogle Scholar
  21. Klesney-Tait, J., I.R. Turnbull, and M. Colonna. 2006. The TREM receptor family and signal integration. Nat Immunol 7: 1266–1273.CrossRefPubMedGoogle Scholar
  22. Koga, T., M. Inui, K. Inoue, S. Kim, A. Suematsu, E. Kobayashi, T. Iwata, H. Ohnishi, T. Matozaki, T. Kodama, et al. 2004. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428: 758–763.CrossRefPubMedGoogle Scholar
  23. Kondo, T., K. Takahashi, N. Kohara, Y. Takahashi, S. Hayashi, H. Takahashi, H. Matsuo, M. Yamazaki, K. Inoue, K. Miyamoto, and T. Yamamura. 2002. Heterogeneity of presenile dementia with bone cysts (Nasu-Hakola disease): Three genetic forms. Neurology 59: 1105–1107.PubMedGoogle Scholar
  24. Lanier, L.L. 2003. Natural killer cell receptor signaling. Curr Opin Immunol 15: 308–314.CrossRefPubMedGoogle Scholar
  25. McVicar, D.W., and Burshtyn, D.N. 2001. Intracellular signaling by the killer immunoglobulin-like receptors and Ly49. Sci STKE 2001, RE1.Google Scholar
  26. Mocsai, A., M.B. Humphrey, J.A. Van Ziffle, Y. Hu, A. Burghardt, S.C. Spusta, S. Majumdar, L.L. Lanier, C.A. Lowell, and M.C. Nakamura. 2004. The immunomodulatory adapter proteins DAP12 and Fc receptor gamma-chain (FcRgamma) regulate development of functional osteoclasts through the Syk tyrosine kinase. Proc Natl Acad Sci U S A 101: 6158–6163.CrossRefPubMedGoogle Scholar
  27. Nadler, M.J., S.A. Matthews, H. Turner, and J.P. Kinet. 2000. Signal transduction by the high-affinity immunoglobulin E receptor Fc epsilon RI: coupling form to function. Adv Immunol 76: 325–355.CrossRefPubMedGoogle Scholar
  28. Nasu, T., Y. Tsukahara, and K. Terayama. 1973. A lipid metabolic disease-“membranous lipodystrophy”-an autopsy case demonstrating numerous peculiar membrane-structures composed of compound lipid in bone and bone marrow and various adipose tissues. Acta Pathol Jpn 23: 539–558.PubMedGoogle Scholar
  29. Paloneva, J., T. Autti, R. Raininko, J. Partanen, O. Salonen, M. Puranen, P. Hakola, and M. Haltia. 2001. CNS manifestations of Nasu-Hakola disease: a frontal dementia with bone cysts. Neurology 56: 1552–1558.PubMedGoogle Scholar
  30. Paloneva, J., M. Kestila, J. Wu, A. Salminen, T. Bohling, V. Ruotsalainen, P. Hakola, A.B. Bakker, J.H. Phillips, P. Pekkarinen, et al. 2000. Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nat Genet 25: 357–361.CrossRefPubMedGoogle Scholar
  31. Paloneva, J., J. Mandelin, A. Kiialainen, T. Bohling, J. Prudlo, P. Hakola, M. Haltia, Y.T. Konttinen, and L. Peltonen. 2003. DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features. J Exp Med 198: 669–675.CrossRefPubMedGoogle Scholar
  32. Paloneva, J., T. Manninen, G. Christman, K. Hovanes, J. Mandelin, R. Adolfsson, M. Bianchin, T. Bird, R. Miranda, A. Salmaggi, et al. 2002. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet 71: 3.CrossRefGoogle Scholar
  33. Pasquier, B., P. Launay, Y. Kanamaru, I.C. Moura, S. Pfirsch, C. Ruffie, D. Henin, M. Benhamou, M. Pretolani, U. Blank, and R.C. Monteiro 2005. Identification of FcalphaRI as an inhibitory receptor that controls inflammation: dual role of FcRgamma ITAM. Immunity 22: 31–42.PubMedGoogle Scholar
  34. Schmid, C.D., L.N. Sautkulis, P.E. Danielson, J. Cooper, K.W. Hasel, B.S. Hilbush, J.G. Sutcliffe, and M.J. Carson. 2002. Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J Neurochem 83: 1309–1320.CrossRefPubMedGoogle Scholar
  35. Sessa, G., P. Podini, M. Mariani, A. Meroni, R. Spreafico, F. Sinigaglia, M. Colonna, P. Panina, and J. Meldolesi. 2004. Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia. Eur J Neurosci 20: 2617–2628.CrossRefPubMedGoogle Scholar
  36. Soragna, D., L. Papi, M.T. Ratti, R. Sestini, R. Tupler, and L. Montalbetti. 2003. An Italian family affected by Nasu-Hakola disease with a novel genetic mutation in the TREM2 gene. J Neurol Neurosurg Psychiatry 74: 825–826.CrossRefPubMedGoogle Scholar
  37. Stefanova, I., B. Hemmer, M. Vergelli, R. Martin, W.E. Biddison, and R.N. Germain. 2003. TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat Immunol 4: 248–254.CrossRefPubMedGoogle Scholar
  38. Takayanagi, H. 2005. Mechanistic insight into osteoclast differentiation in osteoimmunology. J Mol Med 83: 170–179.CrossRefPubMedGoogle Scholar
  39. Takegahara, N., H. Takamatsu, T. Toyofuku, T. Tsujimura, T. Okuno, K. Yukawa, M. Mizui, M. Yamamoto, D.V. Prasad, K. Suzuki, et al. 2006. Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis. Nat Cell Biol 8: 615–622.CrossRefPubMedGoogle Scholar
  40. Teitelbaum, S.L. 2000. Bone resorption by osteoclasts. Science 289: 1504–1508.CrossRefPubMedGoogle Scholar
  41. Turnbull, I.R., S. Gilfillan, M. Cella, T. Aoshi, M. Miller, L. Piccio, M. Hernandez, and M. Colonna. 2006. Cutting edge: TREM-2 attenuates macrophage activation. J Immunol 177: 3520–3524.PubMedGoogle Scholar
  42. Vivier, E., J.A. Nunes, and F. Vely. 2004. Natural killer cell signaling pathways. Science 306: 1517–1519.CrossRefPubMedGoogle Scholar
  43. Walsh, M.C., N. Kim, Y. Kadono, J. Rho, S.Y. Lee, J. Lorenzo, and Y. Choi. 2006. Osteoimmunology: interplay between the immune system and bone metabolism. Annu Rev Immunol 24: 33–63.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Marco Colonna
    • 1
  • Isaiah Turnbull
    • 1
  • Julia Klesney-Tait
    • 1
  1. 1.Department of Pathology and ImmunologyWashington University School of MedicineSt. LouisUSA

Personalised recommendations