J Bone Metab.  2014 Nov;21(4):233-241. 10.11005/jbm.2014.21.4.233.

Regulation of NFATc1 in Osteoclast Differentiation

• Kim JH
• Kim N

• KMID: 2170050
• DOI: http://doi.org/10.11005/jbm.2014.21.4.233

Abstract

Osteoclasts are unique cells that degrade the bone matrix. These large multinucleated cells differentiate from the monocyte/macrophage lineage upon stimulation by two essential cytokines, macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B (NF-kappaB) ligand (RANKL). Activation of transcription factors such as microphthalmia transcription factor (MITF), c-Fos, NF-kappaB, and nuclear factor-activated T cells c1 (NFATc1) is required for sufficient osteoclast differentiation. In particular, NFATc1 plays the role of a master transcription regulator of osteoclast differentiation. To date, several mechanisms, including transcription, methylation, ubiquitination, acetylation, and non-coding RNAs, have been shown to regulate expression and activation of NFATc1. In this review, we have summarized the various mechanisms that control NFATc1 regulation during osteoclast differentiation.

Keyword

Gene expression regulation; NFATc transcription factors; Osteoclasts; RANK ligand

MeSH Terms

Acetylation
Bone Matrix
Cytokines
Gene Expression Regulation
Macrophage Colony-Stimulating Factor
Methylation
Microphthalmos
NF-kappa B
NFATC Transcription Factors
Osteoclasts*
RANK Ligand
Receptor Activator of Nuclear Factor-kappa B
RNA, Untranslated
T-Lymphocytes
Transcription Factors
Ubiquitin
Ubiquitination
Cytokines
Macrophage Colony-Stimulating Factor
NF-kappa B
NFATC Transcription Factors
RANK Ligand
RNA, Untranslated
Receptor Activator of Nuclear Factor-kappa B
Transcription Factors
Ubiquitin

Figure

• 

  Fig. 1 Induction of nuclear factor-activated T cells c1 (NFATc1) in osteoclasts. Receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL) induces the NFATc1 gene via the NF-κB and c-Fos signaling pathway. Cooperation between RANKL and the costimulatory signals for receptor activator of NF-κB (RANK) synergistically activates phospholipase Cγ (PLCγ) and calcium signaling, which are critical for NFATc1 induction and activation. Activation of calcium signaling leads to the recruitment of NFATc1 to its own promoter for the robust induction of NFATc1. In contrast, RANKL downregulates anti-osteoclastogenic genes such as interferon regulatory factor 8 (IRF8), V-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MafB), inhibitors of differentiation (Ids) and LIM homeobox 2 (Lhx2), which inhibit NFATc1 expression mediated by RANKL. RANKL, receptor activator of nuclear factor-kappa B (NF-κB) ligand; OSCAR, osteoclast-associated receptor; PIR-A, paired immunoglobulin-like receptor-A; RANK, receptor activator of nuclear factor-kappa B; TREM-2, triggering receptor expressed in myeloid cells-2; SIRPβ1, signal-regulatory protein β1; TRAF6, tumor necrosis factor receptor-associated factor 6; FcRγ, Fc receptor common γ subunit; DAP12, DNAX-activating protein 12; IRF8, interferon regulatory factor-8; MafB, V-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B; Ids, inhibitors of differentiation; Lhx2, LIM homeobox 2; PLC-γ, phospholipase C-γ; NF-κB, nuclear factor-kappa B; GSK3, glycogen synthase kinase 3; NFATc1, nuclear factor-activated T cells c1.

• 

  Fig. 2 Epigenetic regulation of nuclear factor-activated T cells c1 (NFATc1) in osteoclasts. Macrophage colony-stimulating factor (M-CSF) induces phosphorylation of Cbl-b and c-Cbl in a Src kinase-dependent manner and subsequently induces NFATc1 ubiquitination and proteasomal degradation. Receptor activator of nuclear factor-kappa B ligand (RANKL) induces acetylation of NFATc1 via p300/CBP-associated factor (PCAF), and NFATc1 acetylation induces its stability. This acetylation is reversed by histone deacetylase 5 (HDAC5). RANKL induces the Jmjd3 gene, which enhances demethylation of H3K27me3 at the transcription start site (TSS) of NFATc1 and enhances RANKL-induced NFATc1 expression. RANKL reduces miR-124 expression, which directly targets NFATc1. M-CSF, macrophage colony-stimulating factor; NFATc1, nuclear factor-activated T cells c1; RANKL, receptor activator of nuclear factor-kappa B (NF-κB) ligand; PCAF, cyclic adenosine 3',5'-monophosphate response element-binding protein (CREB)-binding protein (CBP) and p300/CBP-associated factor; HDAC5, histone deacetylase 5; Jmjd3, jumonji domain-containing protein 3; TSS, transcription start site.

Reference

1. Suda T, Takahashi N, Udagawa N, et al. 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.

2. Teitelbaum SL. Bone resorption by osteoclasts. Science. 2000; 289:1504–1508.

3. Walsh MC, Kim N, Kadono Y, et al. Osteoimmunology: interplay between the immune system and bone metabolism. Annu Rev Immunol. 2006; 24:33–63.

4. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003; 423:337–342.

5. Wiktor-Jedrzejczak W, Bartocci A, Ferrante AW Jr, et al. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci U S A. 1990; 87:4828–4832.

6. Yoshida H, Hayashi S, Kunisada T, et al. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature. 1990; 345:442–444.

7. Kong YY, Yoshida H, Sarosi I, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999; 397:315–323.

8. Dougall WC, Glaccum M, Charrier K, et al. RANK is essential for osteoclast and lymph node development. Genes Dev. 1999; 13:2412–2424.

9. Takayanagi H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol. 2007; 7:292–304.

10. Takayanagi H, Kim S, Koga T, et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002; 3:889–901.

11. Matsumoto M, Kogawa M, Wada S, et al. Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATc1 and PU.1. J Biol Chem. 2004; 279:45969–45979.

12. Kim K, Kim JH, Lee J, et al. 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. 2005; 280:35209–35216.

13. Kim Y, Sato K, Asagiri M, et al. 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. 2005; 280:32905–32913.

14. Winslow MM, Pan M, Starbuck M, et al. Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev Cell. 2006; 10:771–782.

15. Aliprantis AO, Ueki Y, Sulyanto R, et al. NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism. J Clin Invest. 2008; 118:3775–3789.

16. Hogan PG, Chen L, Nardone J, et al. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 2003; 17:2205–2232.

17. Graef IA, Chen F, Crabtree GR. NFAT signaling in vertebrate development. Curr Opin Genet Dev. 2001; 11:505–512.

18. Crabtree GR, Olson EN. NFAT signaling: choreographing the social lives of cells. Cell. 2002; 109:Suppl. S67–S79.

19. Kiani A, Habermann I, Haase M, et al. Expression and regulation of NFAT (nuclear factors of activated T cells) in human CD34+ cells: down-regulation upon myeloid differentiation. J Leukoc Biol. 2004; 76:1057–1065.

20. López-Rodríguez C, Aramburu J, Jin L, et al. Bridging the NFAT and NF-kappaB families: NFAT5 dimerization regulates cytokine gene transcription in response to osmotic stress. Immunity. 2001; 15:47–58.

21. Horsley V, Pavlath GK. NFAT: ubiquitous regulator of cell differentiation and adaptation. J Cell Biol. 2002; 156:771–774.

22. Takayanagi H. The role of NFAT in osteoclast formation. Ann N Y Acad Sci. 2007; 1116:227–237.

23. Hodge MR, Ranger AM, Charles de la Brousse F, et al. Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice. Immunity. 1996; 4:397–405.

24. Xanthoudakis S, Viola JP, Shaw KT, et al. An enhanced immune response in mice lacking the transcription factor NFAT1. Science. 1996; 272:892–895.

25. Yoshida H, Nishina H, Takimoto H, et al. The transcription factor NF-ATc1 regulates lymphocyte proliferation and Th2 cytokine production. Immunity. 1998; 8:115–124.

26. Ranger AM, Hodge MR, Gravallese EM, et al. Delayed lymphoid repopulation with defects in IL-4-driven responses produced by inactivation of NF-ATc. Immunity. 1998; 8:125–134.

27. Johnson RS, Spiegelman BM, Papaioannou V. Pleiotropic effects of a null mutation in the c-fos proto-oncogene. Cell. 1992; 71:577–586.

28. Wang ZQ, Ovitt C, Grigoriadis AE, et al. Bone and haematopoietic defects in mice lacking c-fos. Nature. 1992; 360:741–745.

29. Matsuo K, Galson DL, Zhao C, et al. Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos. J Biol Chem. 2004; 279:26475–26480.

30. Asagiri M, Sato K, Usami T, et al. Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med. 2005; 202:1261–1269.

31. Anderson DM, Maraskovsky E, Billingsley WL, et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 1997; 390:175–179.

32. Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell. 2002; 109:Suppl. S81–S96.

33. Hayden MS, Ghosh S. Signaling to NF-kappaB. Genes Dev. 2004; 18:2195–2224.

34. Novack DV, Yin L, Hagen-Stapleton A, et al. The IkappaB function of NF-kappaB2 p100 controls stimulated osteoclastogenesis. J Exp Med. 2003; 198:771–781.

35. Ruocco MG, Maeda S, Park JM, 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.

36. Franzoso G, Carlson L, Xing L, et al. Requirement for NF-kappaB in osteoclast and B-cell development. Genes Dev. 1997; 11:3482–3496.

37. Iotsova V, Caamaño J, Loy J, et al. Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Nat Med. 1997; 3:1285–1289.

38. Takatsuna H, Asagiri M, Kubota T, et al. Inhibition of RANKL-induced osteoclastogenesis by (-)-DHMEQ, a novel NF-kappaB inhibitor, through downregulation of NFATc1. J Bone Miner Res. 2005; 20:653–662.

39. Koga T, Matsui Y, Asagiri M, et al. NFAT and Osterix cooperatively regulate bone formation. Nat Med. 2005; 11:880–885.

40. Lee J, Kim K, Kim JH, et al. Id helix-loop-helix proteins negatively regulate TRANCE-mediated osteoclast differentiation. Blood. 2006; 107:2686–2693.

41. Kim K, Kim JH, Lee J, et al. MafB negatively regulates RANKL-mediated osteoclast differentiation. Blood. 2007; 109:3253–3259.

42. Kim JH, Youn BU, Kim K, et al. Lhx2 regulates bone remodeling in mice by modulating RANKL signaling in osteoclasts. Cell Death Differ. 2014; 21:1613–1621.

43. Kim K, Lee J, Kim JH, et al. Protein inhibitor of activated STAT 3 modulates osteoclastogenesis by down-regulation of NFATc1 and osteoclast-associated receptor. J Immunol. 2007; 178:5588–5594.

44. Zhao B, Takami M, Yamada A, et al. Interferon regulatory factor-8 regulates bone metabolism by suppressing osteoclastogenesis. Nat Med. 2009; 15:1066–1071.

45. Miyauchi Y, Ninomiya K, Miyamoto H, et al. The Blimp1-Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis. J Exp Med. 2010; 207:751–762.

46. Bird A. Perceptions of epigenetics. Nature. 2007; 447:396–398.

47. Yasui T, Hirose J, Aburatani H, et al. Epigenetic regulation of osteoclast differentiation. Ann N Y Acad Sci. 2011; 1240:7–13.

48. Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003; 33:Suppl. 245–254.

49. Yasui T, Hirose J, Tsutsumi S, et al. Epigenetic regulation of osteoclast differentiation: possible involvement of Jmjd3 in the histone demethylation of Nfatc1. J Bone Miner Res. 2011; 26:2665–2671.

50. Bae SC, Lee YH. Phosphorylation, acetylation and ubiquitination: the molecular basis of RUNX regulation. Gene. 2006; 366:58–66.

51. Kim JH, Kim K, Jin HM, et al. Negative feedback control of osteoclast formation through ubiquitin-mediated down-regulation of NFATc1. J Biol Chem. 2010; 285:5224–5231.

52. Kim JH, Kim K, Youn BU, et al. RANKL induces NFATc1 acetylation and stability via histone acetyltransferases during osteoclast differentiation. Biochem J. 2011; 436:253–262.

53. Ambros V. The functions of animal microRNAs. Nature. 2004; 431:350–355.

54. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004; 116:281–297.

55. Chen K, Rajewsky N. The evolution of gene regulation by transcription factors and microRNAs. Nat Rev Genet. 2007; 8:93–103.

56. Kapinas K, Delany AM. MicroRNA biogenesis and regulation of bone remodeling. Arthritis Res Ther. 2011; 13:220.

57. Lee Y, Kim HJ, Park CK, et al. MicroRNA-124 regulates osteoclast differentiation. Bone. 2013; 56:383–389.

58. Mao D, Epple H, Uthgenannt B, et al. PLCgamma2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2. J Clin Invest. 2006; 116:2869–2879.

59. Beals CR, Sheridan CM, Turck CW, et al. Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science. 1997; 275:1930–1934.

60. Chow CW, Rincón M, Cavanagh J, et al. Nuclear accumulation of NFAT4 opposed by the JNK signal transduction pathway. Science. 1997; 278:1638–1641.

61. Okamura H, Garcia-Rodriguez C, Martinson H, et al. A conserved docking motif for CK1 binding controls the nuclear localization of NFAT1. Mol Cell Biol. 2004; 24:4184–4195.

62. Gómez del Arco P, Martínez-Martínez S, Maldonado JL, et al. A role for the p38 MAP kinase pathway in the nuclear shuttling of NFATp. J Biol Chem. 2000; 275:13872–13878.

63. Zhu J, Shibasaki F, Price R, et al. Intramolecular masking of nuclear import signal on NF-AT4 by casein kinase I and MEKK1. Cell. 1998; 93:851–861.

64. Jang HD, Shin JH, Park DR, et al. Inactivation of glycogen synthase kinase-3beta is required for osteoclast differentiation. J Biol Chem. 2011; 286:39043–39050.

65. Koga T, Inui M, Inoue K, et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature. 2004; 428:758–763.

66. Kaifu T, Nakahara J, Inui M, et al. Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J Clin Invest. 2003; 111:323–332.

67. Mócsai A, Humphrey MB, Van Ziffle JA, et al. 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. 2004; 101:6158–6163.