Advertisement

NFATc1 in Inflammatory and Musculoskeletal Conditions

  • Antonios O. AliprantisEmail author
  • Laurie H. Glimcher
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 658)

Abstract

The nuclear factor of activated T-cells (NFAT) family of transcription factors specify developmental pathways and cell fate in vertebrates. NFATc1, in particular, is crucial to multiple seemingly unrelated biologic processes, including heart valve formation, T-cell activation, osteoclast development, and the mitigation of hair follicle stem cell proliferation. Here, we review how our recently generated NFATc1 conditional knockout mouse has contributed to our understanding of this transcription factor in inflammatory and musculoskeletal conditions and their treatment.

Keywords

NFATc1 Osteoclast Hair follicle 

References

  1. 1.
    Aliprantis, A.O., Ueki, Y., Sulyanto, R. et al. (2008). NFATc1 represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism. J Clin Invest, 118(11):377–389.CrossRefGoogle Scholar
  2. 2.
    Arron, J.R., Winslow, M.M., Polleri, A. et al. (2006). NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature, 441:595–600.CrossRefPubMedGoogle Scholar
  3. 3.
    Asagiri, M., & Takayanagi, H. (2007). The molecular understanding of osteoclast differentiation. Bone, 40:251–264.CrossRefPubMedGoogle Scholar
  4. 4.
    Asagiri, M., Sato, K., Usami, T. et al. (2005). Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med, 202:1261–1269.CrossRefPubMedGoogle Scholar
  5. 5.
    Atkins, G.J., Bouralexis, S., Haynes, D.R. et al. (2001). Osteoprotegerin inhibits osteoclast formation and bone resorbing activity in giant cell tumors of bone. Bone, 28:370–377.CrossRefPubMedGoogle Scholar
  6. 6.
    Boyle, W.J., Simonet, W.S., & Lacey, D.L. (2003). Osteoclast differentiation and activation. Nature, 423:337–342.CrossRefPubMedGoogle Scholar
  7. 7.
    Carlsten, H. (2005). Immune responses and bone loss: the estrogen connection. Immunol Rev, 208:194–206.CrossRefPubMedGoogle Scholar
  8. 8.
    Chang, C.P., Neilson, J.R., Bayle, J.H. et al. (2004). A field of myocardial-endocardial NFAT signaling underlies heart valve morphogenesis. Cell, 118:649–663.CrossRefPubMedGoogle Scholar
  9. 9.
    Crotti, T.N., Flannery, M., Walsh, N.C. et al. (2006). NFATc1 regulation of the human beta3 integrin promoter in osteoclast differentiation. Gene, 372:92–102.CrossRefPubMedGoogle Scholar
  10. 10.
    Fuller, K., Wong, B., Fox, S. et al. (1998). TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J.Exp.Med, 188:997–1001.CrossRefPubMedGoogle Scholar
  11. 11.
    Graef, I.A., Chen, F., & Crabtree, G.R. (2001). NFAT signaling in vertebrate development. Curr Opin Genet Dev, 11:505–512.CrossRefPubMedGoogle Scholar
  12. 12.
    Graef, I.A., Wang, F., Charron, F. et al. (2003). Neurotrophins and netrins require calcineurin/NFAT signaling to stimulate outgrowth of embryonic axons. Cell, 113:657–670.CrossRefPubMedGoogle Scholar
  13. 13.
    Gwack, Y., Sharma, S., Nardone, J. et al. (2006). A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature, 441:582–583.CrossRefGoogle Scholar
  14. 14.
    Hirotani, H., Tuohy, N.A., Woo, J.T. et al. (2004). The calcineurin/nuclear factor of activated T cells signaling pathway regulates osteoclastogenesis in RAW264.7 cells. J Biol Chem, 279:13984–13992.CrossRefPubMedGoogle Scholar
  15. 15.
    Hodge, M.R., Ranger, A.M., Charles de la Brousse, F. et al. (1996). Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice. Immunity, 4:397–405.CrossRefPubMedGoogle Scholar
  16. 16.
    Hogan, P.G., Chen, L., Nardone, J. et al. (2003). Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev, 17:2205–2232.CrossRefPubMedGoogle Scholar
  17. 17.
    Horsley, V., Aliprantis, A.O., Polak, L. et al. (2008). NFATc1 balances quiescence and proliferation of skin stem cells. Cell, 132:299–310.CrossRefPubMedGoogle Scholar
  18. 18.
    Jimi, E., & Ghosh, S. (2005). Role of nuclear factor-kappaB in the immune system and bone. Immunol Rev, 208:80–87.CrossRefPubMedGoogle Scholar
  19. 19.
    Kaminuma, O., Kitamura, F., Kitamura, N. et al. (2008). Differential contribution of NFATc2 and NFATc1 to TNF-alpha gene expression in T cells. J Immunol, 180:319–326.PubMedGoogle Scholar
  20. 20.
    Karsenty, G., & Wagner, E.F. (2002). Reaching a genetic and molecular understanding of skeletal development. Dev Cell, 2:389–406.CrossRefPubMedGoogle Scholar
  21. 21.
    Kim, K., Kim, J.H., Lee, J. et al. (2005a). Nuclear factor of activated T cells c1 induces osteoclast-associated receptor gene expression during tumor necrosis factor-related activation-induced cytokine-mediated osteoclastogenesis. J Biol Chem, 280:35209–35216.CrossRefPubMedGoogle Scholar
  22. 22.
    Kim, Y., Sato, K., Asagiri, M. et al. (2005b). Contribution of nuclear factor of activated T cells c1 to the transcriptional control of immunoreceptor osteoclast-associated receptor but not triggering receptor expressed by myeloid cells-2 during osteoclastogenesis. J Biol Chem, 280:32905–32913.CrossRefPubMedGoogle Scholar
  23. 23.
    Koga, T., Inui, M., Inoue, K. et al. (2004). Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature, 428:758–763.CrossRefPubMedGoogle Scholar
  24. 24.
    Kong, Y.Y., Yoshida, H., Sarosi, I. et al. (1999). OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature, 397:315–323.CrossRefPubMedGoogle Scholar
  25. 25.
    Liu, B., Yu, S.F., & Li, T.J. (2003). Multinucleated giant cells in various forms of giant cell containing lesions of the jaws express features of osteoclasts. J Oral Pathol Med, 32:367–375.CrossRefPubMedGoogle Scholar
  26. 26.
    Lorenzo, J., & Choi, Y. (2005). Osteoimmunology. Immunol Rev, 208:5–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Luisde la Pompa, J., Timmerman, L.A., Takimoto, H. et al. (1998). Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum. Nature, 392:182–186.CrossRefGoogle Scholar
  28. 28.
    Peng, S.L., Gerth, A.J., Ranger, A.M. et al. (2001). NFATc1 and NFATc2 together control both T and B cell activation and differentiation. Immunity, 14:13–20.CrossRefPubMedGoogle Scholar
  29. 29.
    Phillips, K., Aliprantis, A., & Coblyn, J. (2006). Strategies for the prevention and treatment of osteoporosis in patients with rheumatoid arthritis. Drugs Aging, 23:773–779.CrossRefPubMedGoogle Scholar
  30. 30.
    Ranger, A.M., Grusby, M.J., Hodge, M.R. et al. (1998a). The transcription factor NF-ATc is essential for cardiac valve formation. Nature, 392:186–190.CrossRefPubMedGoogle Scholar
  31. 31.
    Ranger, A.M., Hodge, M.R., Gravallese, E.M. et al. (1998b). Delayed lymphoid repopulation with defects in IL-4-driven responses produced by inactivation of NFATc. Immunity, 8:125–134.CrossRefPubMedGoogle Scholar
  32. 32.
    Ranger, A.M., Gerstenfeld, L.C., Wang, J. et al. (2000). The transcription factor NFATp is a repressor of chondrogenesis. J Exp Med, 191:9–21.CrossRefPubMedGoogle Scholar
  33. 33.
    Rho, J., Takami, M., & Choi, Y. (2004). Osteoimmunology: interactions of the immune and skeletal systems. Mol Cells, 17:1–9.PubMedGoogle Scholar
  34. 34.
    Sharma, S.M., Bronisz, A., Hu, R. et al. (2007). MITF and PU.1 recruit p38 MAPK and NFATc1 to target genes during osteoclast differentiation. J Biol Chem, 282:15921–15929.CrossRefPubMedGoogle Scholar
  35. 35.
    Shaw, J., Utz, P., Durand, D. et al. (1988). Identification of a putative regulator of early T cell activation genes. Science, 241:202–205.CrossRefPubMedGoogle Scholar
  36. 36.
    Simonet, W.S., Lacey, D.L., Dunstan, C.R. et al. (1997). Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell, 89:309–319.CrossRefPubMedGoogle Scholar
  37. 37.
    Takayanagi, H., Sato, K., Takaoka, A. et al. (2005). Interplay between interferon and other cytokine systems in bone metabolism. Immunol Rev, 208:181–193.CrossRefPubMedGoogle Scholar
  38. 38.
    Takayanagi, H., Kim, S., Koga, T. et al. (2002). Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell, 3:889–901.CrossRefPubMedGoogle Scholar
  39. 39.
    Tanaka, S., Nakamura, K., Takahasi, N. et al. (2005). Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system. Immunol Rev, 208:30–49.CrossRefPubMedGoogle Scholar
  40. 40.
    Tanaka, S., Takahashi, N., Udagawa, N. et al. (1993). Macrophage colony-stimulating factor is indispensable for both proliferation and differentiation of osteoclast progenitors. J Clin Invest, 91:257–263.CrossRefPubMedGoogle Scholar
  41. 41.
    Tolar, J., Teitelbaum, S.L., & Orchard, P.J. (2004). Osteopetrosis. N Engl J Med, 351:2839–2849.CrossRefPubMedGoogle Scholar
  42. 42.
    Tsytsykova, A.V., & Goldfeld, A.E. (2000). Nuclear Factor of Activated T Cells Transcription Factor NFATp Controls Superantigen-induced Lethal Shock. J Exp Med, 192:581–586.CrossRefPubMedGoogle Scholar
  43. 43.
    Ueki, Y., Tiziani, V., Santanna, C. et al. (2001). Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism. Nat Genet, 28:125–126.CrossRefPubMedGoogle Scholar
  44. 44.
    Ueki, Y., Lin, C.Y., Senoo, M. et al. (2007). Increased myeloid cell responses to M-CSF and RANKL cause bone loss and inflammation in SH3BP2 “cherubism” mice. Cell, 128:71–83.CrossRefPubMedGoogle Scholar
  45. 45.
    Wada, T., Nakashima, T., Hiroshi, N. et al. (2006). RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med, 12:17–25.CrossRefPubMedGoogle Scholar
  46. 46.
    Wagner, E.F., & Eferl, R. (2005). Fos/AP-1 proteins in bone and the immune system. Immunol Rev, 208:126–140.CrossRefPubMedGoogle Scholar
  47. 47.
    Wein, M.N., Jones, D.C., & Glimcher, L.H. (2005). Turning down the system: counter-regulatory mechanisms in bone and adaptive immunity. Immunol Rev, 208:66–79.CrossRefPubMedGoogle Scholar
  48. 48.
    Winslow, M.M., Pan, M., Starbuck, M. et al. (2006). Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev Cell, 10:771–782.CrossRefPubMedGoogle Scholar
  49. 49.
    Wu, H., Peisley, A., Graef, I.A. et al. (2007). NFAT signaling and the invention of vertebrates. Trends Cell Biol, 17:251–260.CrossRefPubMedGoogle Scholar
  50. 50.
    Xing, L., Schwarz, E.M., & Boyce, B.F. (2005). Osteoclast precursors, RANKL/RANK, and immunology. Immunol Rev, 208:19–29.CrossRefPubMedGoogle Scholar
  51. 51.
    Yamamoto, S., & Kato, R. (1994). Hair growth-stimulating effects of cyclosporin A and FK506, potent immunosuppressants. J Dermatol Sci, 7(Suppl):S47–S54.CrossRefPubMedGoogle Scholar
  52. 52.
    Yasuda, H., Shima, N., Nakagawa, N. 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, 95:3597–3602.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Medicine, Division of Rheumatology, Allergy and Immunology and Department of Infectious Disease and ImmunologyHarvard Medical School, Brigham and Women’s Hospital, Harvard School of Public HealthBostonUSA
  2. 2.Department of Infectious Disease and Immunology and Department of Medicine, Division of Rheumatology, Allergy and ImmunologyHarvard School of Public Health, Harvard Medical School and Brigham and Women’s HospitalBostonUSA

Personalised recommendations