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Histochemistry and Cell Biology

, Volume 149, Issue 4, pp 325–341 | Cite as

Recent advances in osteoclast biology

  • Takehito Ono
  • Tomoki Nakashima
Review

Abstract

The bone is an essential organ for locomotion and protection of the body, as well as hematopoiesis and mineral homeostasis. In order to exert these functions throughout life, bone tissue undergoes a repeating cycle of osteoclastic bone resorption and osteoblastic bone formation. The osteoclast is a large, multinucleated cell that is differentiated from monocyte/macrophage lineage cells by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). RANKL transduces its signal through the signaling receptor, RANK. RANKL/RANK signaling activates NFATc1, the master regulator of osteoclastogenesis, to induce osteoclastogenic gene expression. Many types of cells express RANKL to support osteoclastogenesis depending on the biological context and the dysregulation of RANKL signaling leads to bone diseases such as osteoporosis and osteopetrosis. This review outlines the findings on osteoclast and RANKL/RANK signaling that have accumulated to date.

Keywords

Osteoclast RANKL RANK Bone diseases 

Notes

Acknowledgements

This work was supported by Ichiro Kanehara Foundation, Lotte Research Promotion Grant, Takeda Science Foundation, The Uehara Memorial Foundation, Japan Agency for Medical Research and Development (AMED, award number: JP17gm0810003), Japan Society for the Promotion of Science (JSPS), Naito Foundation, Astellas Foundation for Research on Metabolic Disorders, Sumitomo Foundation, Asahi Glass Foundation, Daiichi Sankyo Foundation of Life Science, Secom Science and Technology Foundation (SSTF), Mochida Memorial Foundation for Medical and Pharmaceutical Research, Terumo Foundation and Matsui Life Social Welfare Foundation.

References

  1. Ahlberg PE, Clack JA, Blom H (2005) The axial skeleton of the Devonian tetrapod. Ichthyostega Nat 437:137–140.  https://doi.org/10.1038/nature03893 CrossRefGoogle Scholar
  2. Ahlberg PE, Clack JA, Luksevics E, Blom H, Zupins I (2008) Ventastega curonica and the origin of tetrapod morphology. Nature 453:1199–1204.  https://doi.org/10.1038/nature06991 PubMedCrossRefGoogle Scholar
  3. Aliprantis AO et al (2008) NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism. J Clin Invest 118:3775–3789.  https://doi.org/10.1172/JCI35711 PubMedPubMedCentralCrossRefGoogle Scholar
  4. Alnaeeli M, Penninger JM, Teng YT (2006) Immune interactions with CD4 + T cells promote the development of functional osteoclasts from murine CD11c + dendritic cells. J Immunol (Baltimore., Md: 1950) 177:3314–3326CrossRefGoogle Scholar
  5. Anderson DM et al (1997) A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390:175–179.  https://doi.org/10.1038/36593 PubMedCrossRefGoogle Scholar
  6. Aoki K et al (2006) A TNF receptor loop peptide mimic blocks RANK ligand-induced signaling, bone resorption, and bone loss. J Clin Invest 116:1525–1534.  https://doi.org/10.1172/JCI22513 PubMedPubMedCentralCrossRefGoogle Scholar
  7. Arai F et al (1999) Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor kappaB (RANK) receptors. J Exp Med 190:1741–1754PubMedPubMedCentralCrossRefGoogle Scholar
  8. Asagiri M et al (2005) Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med 202:1261–1269.  https://doi.org/10.1084/jem.20051150 PubMedPubMedCentralCrossRefGoogle Scholar
  9. Bai S et al (2005) FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner. J Clin Invest 115:2742–2751.  https://doi.org/10.1172/JCI24921 PubMedPubMedCentralCrossRefGoogle Scholar
  10. Bassett JH, Williams GR (2016) Role of thyroid hormones in skeletal development and bone maintenance. Endocr Rev 37:135–187.  https://doi.org/10.1210/er.2015-1106 PubMedPubMedCentralCrossRefGoogle Scholar
  11. Bohm C et al. (2009) The alpha-isoform of p38 MAPK specifically regulates arthritic bone loss. J Immunol (Baltimore., Md: 1950) 183:5938–5947  https://doi.org/10.4049/jimmunol.0901026 CrossRefGoogle Scholar
  12. Bonewald L (2014) Eighth bone quality seminar proceedings 2013. Osteoporos Int 25 Suppl 3:S465–S501.  https://doi.org/10.1007/s00198-014-2681-x Google Scholar
  13. Boyce BF, Yoneda T, Lowe C, Soriano P, Mundy GR (1992) Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice. J Clin Investig 90:1622–1627.  https://doi.org/10.1172/JCI116032 PubMedPubMedCentralCrossRefGoogle Scholar
  14. Boyle DL et al (2014) Differential roles of MAPK kinases MKK3 and MKK6 in osteoclastogenesis and bone loss. PLoS One 9:e84818.  https://doi.org/10.1371/journal.pone.0084818 PubMedPubMedCentralCrossRefGoogle Scholar
  15. Bucay N et al (1998) Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12:1260–1268PubMedPubMedCentralCrossRefGoogle Scholar
  16. Cao H et al (2010) Activating transcription factor 4 regulates osteoclast differentiation in mice. J Clin Invest 120:2755–2766.  https://doi.org/10.1172/JCI42106 PubMedPubMedCentralCrossRefGoogle Scholar
  17. Chalhoub N et al (2003) Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human. Nat Med 9:399–406.  https://doi.org/10.1038/nm842 PubMedCrossRefGoogle Scholar
  18. Chatani M et al (2015) Microgravity promotes osteoclast activity in medaka fish reared at the international space station. Sci Rep 5:14172.  https://doi.org/10.1038/srep14172 PubMedPubMedCentralCrossRefGoogle Scholar
  19. Chatani M et al (2016) Acute transcriptional up-regulation specific to osteoblasts/osteoclasts in medaka fish immediately after exposure to microgravity. Sci Rep 6:39545.  https://doi.org/10.1038/srep39545 PubMedPubMedCentralCrossRefGoogle Scholar
  20. Chen X, Zhang K, Hock J, Wang C, Yu X (2016) Enhanced but hypofunctional osteoclastogenesis in an autosomal dominant osteopetrosis type II case carrying a c.1856C > T mutation in CLCN7. Bone Res 4:16035.  https://doi.org/10.1038/boneres.2016.35 PubMedPubMedCentralCrossRefGoogle Scholar
  21. Cleiren E et al (2001) Albers–Schönberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum Mol Genet 10:2861–2867.  https://doi.org/10.1093/hmg/10.25.2861 PubMedCrossRefGoogle Scholar
  22. Cong Q et al (2017) p38alpha MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner. Sci Rep 7:45964.  https://doi.org/10.1038/srep45964 PubMedPubMedCentralCrossRefGoogle Scholar
  23. Corral DA et al. (1998) Dissociation between bone resorption and bone formation in osteopenic transgenic mice. Proc Natl Acad Sci 95:13835–13840.  https://doi.org/10.1073/pnas.95.23.13835 PubMedPubMedCentralCrossRefGoogle Scholar
  24. Coudert AE, de Vernejoul MC, Muraca M, Del Fattore A (2015) Osteopetrosis and its relevance for the discovery of new functions associated with the skeleton. Int J Endocrinol 2015:372156.  https://doi.org/10.1155/2015/372156 PubMedPubMedCentralCrossRefGoogle Scholar
  25. Cox TR et al (2015) The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature 522:106–110.  https://doi.org/10.1038/nature14492 PubMedPubMedCentralCrossRefGoogle Scholar
  26. 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 115:4317–4325PubMedCrossRefGoogle Scholar
  27. Decker CE et al (2015) Tmem178 acts in a novel negative feedback loop targeting NFATc1 to regulate bone mass. Proc Natl Acad Sci USA 112:15654–15659.  https://doi.org/10.1073/pnas.1511285112 PubMedPubMedCentralGoogle Scholar
  28. Dougall WC et al (1999) RANK is essential for osteoclast and lymph node development. Genes Dev 13:2412–2424PubMedPubMedCentralCrossRefGoogle Scholar
  29. Edwards JR, Mundy GR (2011) Advances in osteoclast biology: old findings and new insights from mouse models. Nat Rev Rheumatol 7:235–243.  https://doi.org/10.1038/nrrheum.2011.23 PubMedCrossRefGoogle Scholar
  30. Einhorn TA, Gerstenfeld LC (2015) Fracture healing: mechanisms and interventions. Nat Rev Rheumatol 11:45–54.  https://doi.org/10.1038/nrrheum.2014.164 PubMedCrossRefGoogle Scholar
  31. Faccio R et al (2005) Vav3 regulates osteoclast function and bone mass. Nat Med 11:284–290.  https://doi.org/10.1038/nm1194 PubMedCrossRefGoogle Scholar
  32. Franzoso G et al (1997) Requirement for NF-kappaB in osteoclast and B-cell development. Genes Dev 11:3482–3496PubMedPubMedCentralCrossRefGoogle Scholar
  33. Fuller K, Wong B, Fox S, Choi Y, Chambers TJ (1998) TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med 188:997–1001.  https://doi.org/10.1084/jem.188.5.997 PubMedPubMedCentralCrossRefGoogle Scholar
  34. Gelb BD, Shi GP, Chapman HA, Desnick RJ (1996) Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science (New York, NY) 273:1236–1238CrossRefGoogle Scholar
  35. Ghosh S, Karin M (2002) Missing pieces in the NF-kappaB puzzle. Cell 109 Suppl:S81–S96PubMedCrossRefGoogle Scholar
  36. Hayashi M, Nakashima T, Taniguchi M, Kodama T, Kumanogoh A, Takayanagi H (2012) Osteoprotection by semaphorin 3A. Nature 485:69–74.  https://doi.org/10.1038/nature11000 PubMedCrossRefGoogle Scholar
  37. Hikita A et al (2006) Negative regulation of osteoclastogenesis by ectodomain shedding of receptor activator of NF-kappaB ligand. J Biol Chem 281:36846–36855.  https://doi.org/10.1074/jbc.M606656200 PubMedCrossRefGoogle Scholar
  38. Hirotani H, Tuohy NA, Woo JT, Stern PH, Clipstone NA (2004) The calcineurin/nuclear factor of activated T cells signaling pathway regulates osteoclastogenesis in RAW264.7 cells. J Biol Chem 279:13984–13992.  https://doi.org/10.1074/jbc.M213067200 PubMedCrossRefGoogle Scholar
  39. Inaoka T, Bilbe G, Ishibashi O, Tezuka K, Kumegawa M, Kokubo T (1995) Molecular cloning of human cDNA for cathepsin K: novel cysteine proteinase predominantly expressed in bone. Biochem Biophys Res Commun 206:89–96.  https://doi.org/10.1006/bbrc.1995.1013 PubMedCrossRefGoogle Scholar
  40. Irie A, Yamamoto K, Miki Y, Murakami M (2017) Phosphatidylethanolamine dynamics are required for osteoclast fusion. Sci Rep 7:46715.  https://doi.org/10.1038/srep46715 PubMedPubMedCentralCrossRefGoogle Scholar
  41. Ishibashi O, Inui T, Mori Y, Kurokawa T, Kokubo T, Kumegawa M (2001) Quantification of the expression levels of lysosomal cysteine proteinases in purified human osteoclastic cells by competitive RT-PCR. Calcif Tissue Int 68:109–116.  https://doi.org/10.1007/bf02678149 PubMedCrossRefGoogle Scholar
  42. Ishii M et al (2009) Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. Nature 458:524–528.  https://doi.org/10.1038/nature07713 PubMedPubMedCentralCrossRefGoogle Scholar
  43. Ishii M, Kikuta J, Shimazu Y, Meier-Schellersheim M, Germain RN (2010) Chemorepulsion by blood S1P regulates osteoclast precursor mobilization and bone remodeling in vivo. J Exp Med 207:2793–2798.  https://doi.org/10.1084/jem.20101474 PubMedPubMedCentralCrossRefGoogle Scholar
  44. Izawa T, Zou W, Chappel JC, Ashley JW, Feng X, Teitelbaum SL (2012) c-Src links a RANK/alphavbeta3 integrin complex to the osteoclast cytoskeleton. Mol Cell Biol 32:2943–2953.  https://doi.org/10.1128/MCB.00077-12 PubMedPubMedCentralCrossRefGoogle Scholar
  45. Joyce-Shaikh B et al (2010) Myeloid DAP12-associating lectin (MDL)-1 regulates synovial inflammation and bone erosion associated with autoimmune arthritis. J Exp Med 207:579–589.  https://doi.org/10.1084/jem.20090516 PubMedPubMedCentralCrossRefGoogle Scholar
  46. Kaifu T et al (2003) Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J Clin Invest 111:323–332.  https://doi.org/10.1172/JCI16923 PubMedPubMedCentralCrossRefGoogle Scholar
  47. Kameda Y et al (2013) Siglec-15 regulates osteoclast differentiation by modulating RANKL-induced phosphatidylinositol 3-kinase/Akt and Erk pathways in association with signaling Adaptor DAP12. J Bone Miner Res 28:2463–2475.  https://doi.org/10.1002/jbmr.1989 PubMedCrossRefGoogle Scholar
  48. Kenner L et al (2004) Mice lacking JunB are osteopenic due to cell-autonomous osteoblast and osteoclast defects. J Cell Biol 164:613–623.  https://doi.org/10.1083/jcb.200308155 PubMedPubMedCentralCrossRefGoogle Scholar
  49. Kim N et al (2005) Osteoclast differentiation independent of the TRANCE-RANK-TRAF6 axis. J Exp Med 202:589–595.  https://doi.org/10.1084/jem.20050978 PubMedPubMedCentralCrossRefGoogle Scholar
  50. Kim K et al (2007) MafB negatively regulates RANKL-mediated osteoclast differentiation. Blood 109:3253–3259.  https://doi.org/10.1182/blood-2006-09-048249 PubMedCrossRefGoogle Scholar
  51. Kim K, Lee SH, Ha Kim J, Choi Y, Kim N (2008) NFATc1 induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP). Mol Endocrinol 22:176–185.  https://doi.org/10.1210/me.2007-0237 PubMedCrossRefGoogle Scholar
  52. Kim H et al (2013) Tmem64 modulates calcium signaling during RANKL-mediated osteoclast differentiation. Cell Metab 17:249–260.  https://doi.org/10.1016/j.cmet.2013.01.002 PubMedPubMedCentralCrossRefGoogle Scholar
  53. Koga T et al (2004) Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428:758–763.  https://doi.org/10.1038/nature02444 PubMedCrossRefGoogle Scholar
  54. Kong YY et al (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397:315–323.  https://doi.org/10.1038/16852 PubMedCrossRefGoogle Scholar
  55. Kornak U et al (2001) Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell 104:205–215.  https://doi.org/10.1016/S0092-8674(01)00206-9 PubMedCrossRefGoogle Scholar
  56. Kukita T et al (2004) RANKL-induced DC-STAMP is essential for osteoclastogenesis. J Exp Med 200:941–946.  https://doi.org/10.1084/jem.20040518 PubMedPubMedCentralCrossRefGoogle Scholar
  57. Kukita A et al (2011) The transcription factor FBI-1/OCZF/LRF is expressed in osteoclasts and regulates RANKL-induced osteoclast formation in vitro and in vivo. Arthritis Rheum 63:2744–2754.  https://doi.org/10.1002/art.30455 PubMedCrossRefGoogle Scholar
  58. Lacey DL et al (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176PubMedCrossRefGoogle Scholar
  59. Lam J, Nelson CA, Ross FP, Teitelbaum SL, Fremont DH (2001) Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor–ligand specificity. J Clin Invest 108:971–979.  https://doi.org/10.1172/JCI13890 PubMedPubMedCentralCrossRefGoogle Scholar
  60. Lamothe B, Webster WK, Gopinathan A, Besse A, Campos AD, Darnay BG (2007) TRAF6 ubiquitin ligase is essential for RANKL signaling and osteoclast differentiation. Biochem Biophys Res Commun 359:1044–1049.  https://doi.org/10.1016/j.bbrc.2007.06.017 PubMedPubMedCentralCrossRefGoogle Scholar
  61. Lamothe B, Lai Y, Xie M, Schneider MD, Darnay BG (2013) TAK1 is essential for osteoclast differentiation and is an important modulator of cell death by apoptosis and necroptosis. Mol Cell Biol 33:582–595.  https://doi.org/10.1128/MCB.01225-12 PubMedPubMedCentralCrossRefGoogle Scholar
  62. Lange PF, Wartosch L, Jentsch TJ, Fuhrmann JC (2006) ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function. Nature 440:220–223.  https://doi.org/10.1038/nature04535 PubMedCrossRefGoogle Scholar
  63. Lee SH et al (2006) v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation. Nat Med 12:1403–1409.  https://doi.org/10.1038/nm1514 PubMedCrossRefGoogle Scholar
  64. Li YP, Chen W, Liang Y, Li E, Stashenko P (1999) Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification. Nat Genet 23:447–451.  https://doi.org/10.1038/70563 PubMedCrossRefGoogle Scholar
  65. Li J et al (2000) RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA 97:1566–1571PubMedPubMedCentralCrossRefGoogle Scholar
  66. Liu C et al. (2010) Structural and functional insights of RANKL-RANK interaction and signaling. J Immunol (Baltimore., Md: 1950) 184:6910–6919  https://doi.org/10.4049/jimmunol.0904033 CrossRefGoogle Scholar
  67. Lomaga MA et al (1999) TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev 13:1015–1024PubMedPubMedCentralCrossRefGoogle Scholar
  68. Lotinun S et al (2013) Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation. J Clin Invest 123:666–681.  https://doi.org/10.1172/JCI64840 PubMedPubMedCentralGoogle Scholar
  69. Lum L et al (1999) Evidence for a role of a tumor necrosis factor-α (TNF-α)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival. J Biol Chem 274:13613–13618.  https://doi.org/10.1074/jbc.274.19.13613 PubMedCrossRefGoogle Scholar
  70. Maeda H et al (2016) Real-time intravital imaging of pH variation associated with osteoclast activity. Nat Chem Biol 12:579–585.  https://doi.org/10.1038/nchembio.2096 PubMedCrossRefGoogle Scholar
  71. Margolis DS, Szivek JA, Lai LW, Lien YH (2008) Phenotypic characteristics of bone in carbonic anhydrase II-deficient mice. Calcif Tissue Int 82:66–76.  https://doi.org/10.1007/s00223-007-9098-x PubMedCrossRefGoogle Scholar
  72. Maruyama K et al (2012) The transcription factor Jdp2 controls bone homeostasis and antibacterial immunity by regulating osteoclast and neutrophil differentiation. Immunity 37:1024–1036.  https://doi.org/10.1016/j.immuni.2012.08.022 PubMedCrossRefGoogle Scholar
  73. Matsumoto M et al (2004) 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 279:45969–45979.  https://doi.org/10.1074/jbc.M408795200 PubMedCrossRefGoogle Scholar
  74. Matsuo K et al (2004) Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos. J Biol Chem 279:26475–26480.  https://doi.org/10.1074/jbc.M313973200 PubMedCrossRefGoogle Scholar
  75. Min H et al (2000) Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis. J Exp Med 192:463–474PubMedPubMedCentralCrossRefGoogle Scholar
  76. Miyamoto H et al (2012) Osteoclast stimulatory transmembrane protein and dendritic cell-specific transmembrane protein cooperatively modulate cell–cell fusion to form osteoclasts and foreign body giant cells. J Bone Miner Res 27:1289–1297.  https://doi.org/10.1002/jbmr.1575 PubMedCrossRefGoogle Scholar
  77. Miyauchi Y et al (2010) The Blimp1-Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis. J Exp Med 207:751–762.  https://doi.org/10.1084/jem.20091957 PubMedPubMedCentralCrossRefGoogle Scholar
  78. Mizukami J, Takaesu G, Akatsuka H, Sakurai H, Ninomiya-Tsuji J, Matsumoto K, Sakurai N (2002) Receptor activator of NF- B ligand (RANKL) activates TAK1 mitogen-activated protein kinase kinase kinase through a signaling complex containing RANK, TAB2, and TRAF6. Mol Cell Biol 22:992–1000.  https://doi.org/10.1128/mcb.22.4.992-1000.2002 PubMedPubMedCentralCrossRefGoogle Scholar
  79. Mizuno A et al (1998) Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun 247:610–615PubMedCrossRefGoogle Scholar
  80. Nagashima K et al (2017) Identification of subepithelial mesenchymal cells that induce IgA and diversify gut microbiota. Nat Immunol 18:675–682.  https://doi.org/10.1038/ni.3732 PubMedCrossRefGoogle Scholar
  81. Naito A et al (1999) Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells Devot Mol Cell Mech 4:353–362CrossRefGoogle Scholar
  82. Nakagawa N et al (1998) RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem Biophys Res Commun 253:395–400.  https://doi.org/10.1006/bbrc.1998.9788 PubMedCrossRefGoogle Scholar
  83. Nakashima T, Kobayashi Y, Yamasaki S, Kawakami A, Eguchi K, Sasaki H, Sakai H (2000) 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 275:768–775.  https://doi.org/10.1006/bbrc.2000.3379 PubMedCrossRefGoogle Scholar
  84. Nakashima T et al (2011) Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 17:1231–1234.  https://doi.org/10.1038/nm.2452 PubMedCrossRefGoogle Scholar
  85. Negishi-Koga T et al (2015) Immune complexes regulate bone metabolism through FcRgamma signalling. Nat Commun 6:6637.  https://doi.org/10.1038/ncomms7637 PubMedCrossRefGoogle Scholar
  86. Nelson CA, Warren JT, Wang MW, Teitelbaum SL, Fremont DH (2012) RANKL employs distinct binding modes to engage RANK and the osteoprotegerin decoy receptor. Structure 20:1971–1982.  https://doi.org/10.1016/j.str.2012.08.030 PubMedPubMedCentralCrossRefGoogle Scholar
  87. Nguyen AM, Jacobs CR (2013) Emerging role of primary cilia as mechanosensors in osteocytes. Bone 54:196–204.  https://doi.org/10.1016/j.bone.2012.11.016 PubMedCrossRefGoogle Scholar
  88. Nishikawa K et al (2010) Blimp1-mediated repression of negative regulators is required for osteoclast differentiation. Proc Natl Acad Sci USA 107:3117–3122.  https://doi.org/10.1073/pnas.0912779107 PubMedPubMedCentralCrossRefGoogle Scholar
  89. Nishikawa K et al (2015) DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S-adenosylmethionine-producing metabolic pathway. Nat Med 21:281–287.  https://doi.org/10.1038/nm.3774 PubMedCrossRefGoogle Scholar
  90. Ogata N, Kawaguchi H, Chung UI, Roth SI, Segre GV (2007) Continuous activation of G alpha q in osteoblasts results in osteopenia through impaired osteoblast differentiation. J Biol Chem 282:35757–35764.  https://doi.org/10.1074/jbc.M611902200 PubMedCrossRefGoogle Scholar
  91. Okamoto K et al (2017) Osteoimmunology: the conceptual framework unifying the immune and skeletal systems. Physiol Rev 97:1295–1349.  https://doi.org/10.1152/physrev.00036.2016 PubMedCrossRefGoogle Scholar
  92. Ono T, Takayanagi H (2017) Osteoimmunology in bone fracture healing. Curr Osteoporos Rep 15:367–375.  https://doi.org/10.1007/s11914-017-0381-0 PubMedCrossRefGoogle Scholar
  93. Ozaki Y et al (2017) Treatment of OPG-deficient mice with WP9QY, a RANKL-binding peptide, recovers alveolar bone loss by suppressing osteoclastogenesis and enhancing osteoblastogenesis. PLoS One 12:e0184904.  https://doi.org/10.1371/journal.pone.0184904 PubMedPubMedCentralCrossRefGoogle Scholar
  94. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612.  https://doi.org/10.1002/jcc.20084 PubMedCrossRefGoogle Scholar
  95. Pilz GA et al (2011) Human mesenchymal stromal cells express CD14 cross-reactive epitopes. Cytometry A 79:635–645.  https://doi.org/10.1002/cyto.a.21073 PubMedCrossRefGoogle Scholar
  96. Qin A, Cheng TS, Pavlos NJ, Lin Z, Dai KR, Zheng MH (2012) V-ATPases in osteoclasts: structure, function and potential inhibitors of bone resorption. Int J Biochem Cell Biol 44:1422–1435.  https://doi.org/10.1016/j.biocel.2012.05.014 PubMedCrossRefGoogle Scholar
  97. Rodan GA, Martin TJ (1981) Role of osteoblasts in hormonal control of bone resorption—a hypothesis. Calcif Tissue Int 33:349–351.  https://doi.org/10.1007/bf02409454 PubMedCrossRefGoogle Scholar
  98. Ruocco MG et al (2005) I{kappa}B kinase (IKK){beta}, but not IKK{alpha}, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss. J Exp Med 201:1677–1687.  https://doi.org/10.1084/jem.20042081 PubMedPubMedCentralCrossRefGoogle Scholar
  99. Sato K et al (2006) Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nat Med 12:1410–1416.  https://doi.org/10.1038/nm1515 PubMedCrossRefGoogle Scholar
  100. Scimeca JC et al (2000) The gene encoding the mouse homologue of the human osteoclast-specific 116-kDa V-ATPase subunit bears a deletion in osteosclerotic (oc/oc) mutants. Bone 26:207–213.  https://doi.org/10.1016/S8756-3282(99)00278-1 PubMedCrossRefGoogle Scholar
  101. Seita J, Weissman IL (2010) Hematopoietic stem cell: self-renewal versus differentiation. Wiley Interdiscip Rev Syst Biol Med 2:640–653.  https://doi.org/10.1002/wsbm.86 PubMedPubMedCentralCrossRefGoogle Scholar
  102. Shinohara M et al (2008) Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell 132:794–806.  https://doi.org/10.1016/j.cell.2007.12.037 PubMedCrossRefGoogle Scholar
  103. Shoji-Matsunaga A, Ono T, Hayashi M, Takayanagi H, Moriyama K, Nakashima T (2017) Osteocyte regulation of orthodontic force-mediated tooth movement via RANKL expression. Sci Rep 7:8753.  https://doi.org/10.1038/s41598-017-09326-7 PubMedPubMedCentralCrossRefGoogle Scholar
  104. Simonet WS et al (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319PubMedCrossRefGoogle Scholar
  105. Sly WS, Hewett-Emmett D, Whyte MP, Yu YS, Tashian RE (1983) Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. Proc Natl Acad Sci USA 80:2752–2756PubMedPubMedCentralCrossRefGoogle Scholar
  106. Soriano P, Montgomery C, Geske R, Bradley A (1991) Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64:693–702PubMedCrossRefGoogle Scholar
  107. Speziani C et al (2007) Murine dendritic cell transdifferentiation into osteoclasts is differentially regulated by innate and adaptive cytokines. Eur J Immunol 37:747–757.  https://doi.org/10.1002/eji.200636534 PubMedCrossRefGoogle Scholar
  108. 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 20:345–357.  https://doi.org/10.1210/edrv.20.3.0367 PubMedCrossRefGoogle Scholar
  109. Sumiya E et al (2015) Phosphoproteomic analysis of kinase-deficient mice reveals multiple TAK1 targets in osteoclast differentiation. Biochem Biophys Res Commun 463:1284–1290.  https://doi.org/10.1016/j.bbrc.2015.06.105 PubMedCrossRefGoogle Scholar
  110. Takahashi N et al (1988) Osteoblastic cells are involved in osteoclast formation. Endocrinology 123:2600–2602.  https://doi.org/10.1210/endo-123-5-2600 PubMedCrossRefGoogle Scholar
  111. Takano-Yamamoto T (2014) Osteocyte function under compressive mechanical force. Jpn Dental Sci Rev 50:29–39.  https://doi.org/10.1016/j.jdsr.2013.10.004 CrossRefGoogle Scholar
  112. Takayanagi H et al (2002) Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 3:889–901PubMedCrossRefGoogle Scholar
  113. Takegahara N et al (2006) Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis. Nat Cell Biol 8:615–622.  https://doi.org/10.1038/ncb1416 PubMedCrossRefGoogle Scholar
  114. Tanaka S (2017) RANKL-independent osteoclastogenesis: a long-standing controversy. J Bone Miner Res 32:431–433.  https://doi.org/10.1002/jbmr.3092 PubMedCrossRefGoogle Scholar
  115. Tezuka K et al (1994) Molecular cloning of a possible cysteine proteinase predominantly expressed in osteoclasts. J Biol Chem 269:1106–1109PubMedGoogle Scholar
  116. Tsuda E, Goto M, Mochizuki S-i, Yano K, Kobayashi F, Morinaga T, Higashio K (1997) Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem Biophys Res Commun 234:137–142.  https://doi.org/10.1006/bbrc.1997.6603 PubMedCrossRefGoogle Scholar
  117. Tsuji-Takechi K et al (2012) Stage-specific functions of leukemia/lymphoma-related factor (LRF) in the transcriptional control of osteoclast development. Proc Natl Acad Sci USA 109:2561–2566.  https://doi.org/10.1073/pnas.1116042109 PubMedPubMedCentralCrossRefGoogle Scholar
  118. Tsukasaki M et al (2017) LOX fails to substitute for RANKL in osteoclastogenesis. J Bone Miner Res 32:434–439.  https://doi.org/10.1002/jbmr.2990 PubMedCrossRefGoogle Scholar
  119. Turner CH et al. (2009) Mechanobiology of the Skeleton. Sci Signal 2:3CrossRefGoogle Scholar
  120. Udagawa N et al (1989) The bone marrow-derived stromal cell lines MC3T3-G2/PA6 and ST2 support osteoclast-like cell differentiation in cocultures with mouse spleen. Cells Endocrinol 125:1805–1813.  https://doi.org/10.1210/endo-125-4-1805 CrossRefGoogle Scholar
  121. Vu TH et al (1998) MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93:411–422.  https://doi.org/10.1016/S0092-8674(00)81169-1 PubMedPubMedCentralCrossRefGoogle Scholar
  122. Wada T, Nakashima T, Oliveira-dos-Santos AJ, Gasser J, Hara H, Schett G, Penninger JM (2005) The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis. Nat Med 11:394–399.  https://doi.org/10.1038/nm1203 PubMedCrossRefGoogle Scholar
  123. Walsh MC, Choi Y (2014) Biology of the RANKL-RANK-OPG system in immunity bone beyond. Front Immunol 5:511.  https://doi.org/10.3389/fimmu.2014.00511 PubMedPubMedCentralCrossRefGoogle Scholar
  124. Weinstein RS et al (2002) Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids. J Clin Invest 109:1041–1048.  https://doi.org/10.1172/jci14538 PubMedPubMedCentralCrossRefGoogle Scholar
  125. Whyte MP, Mumm S (2004) Heritable disorders of the RANKL/OPG/RANK signaling pathway. J Musculoskelet Neuronal Interact 4:254–267PubMedGoogle Scholar
  126. Winn N, Lalam R, Cassar-Pullicino V (2017) Imaging of Paget’s disease of bone. Wien Med Wochenschr 167:9–17.  https://doi.org/10.1007/s10354-016-0517-3 PubMedCrossRefGoogle Scholar
  127. Wright HL, McCarthy HS, Middleton J, Marshall MJ (2009) RANK, RANKL and osteoprotegerin in bone biology and disease. Curr Rev Musculoskelet Med 2:56–64.  https://doi.org/10.1007/s12178-009-9046-7 PubMedPubMedCentralCrossRefGoogle Scholar
  128. Wu J, Glimcher LH, Aliprantis AO (2008) HCO3-/Cl- anion exchanger SLC4A2 is required for proper osteoclast differentiation and function. Proc Natl Acad Sci USA 105:16934–16939.  https://doi.org/10.1073/pnas.0808763105 PubMedPubMedCentralCrossRefGoogle Scholar
  129. Xiao Y et al (2013) Osteoclast precursors in murine bone marrow express CD27 and are impeded in osteoclast development by CD70 on activated immune cells. Proc Natl Acad Sci USA 110:12385–12390.  https://doi.org/10.1073/pnas.1216082110 PubMedPubMedCentralCrossRefGoogle Scholar
  130. Xiao Y, Palomero J, Grabowska J, Wang L, de Rink I, van Helvert L, Borst J (2017) Macrophages and osteoclasts stem from a bipotent progenitor downstream of a macrophage/osteoclast/dendritic cell progenitor Blood Advances. 1:1993–2006  https://doi.org/10.1182/bloodadvances.2017008540
  131. Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O’Brien CA (2011) Matrix-embedded cells control osteoclast formation. Nat Med 17:1235–1241.  https://doi.org/10.1038/nm.2448 PubMedPubMedCentralCrossRefGoogle Scholar
  132. Xiong J et al (2015) Osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling Bone. PLoS One 10:e0138189.  https://doi.org/10.1371/journal.pone.0138189 PubMedPubMedCentralCrossRefGoogle Scholar
  133. Yagi M et al (2005) DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells. J Exp Med 202:345–351.  https://doi.org/10.1084/jem.20050645 PubMedPubMedCentralCrossRefGoogle Scholar
  134. Yamamoto A et al (2002) Possible involvement of IkappaB kinase 2 and MKK7 in osteoclastogenesis induced by receptor activator of nuclear factor kappaB ligand. J Bone Miner Res 17:612–621.  https://doi.org/10.1359/jbmr.2002.17.4.612 PubMedCrossRefGoogle Scholar
  135. Yamashita T et al (2007) NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. J Biol Chem 282:18245–18253.  https://doi.org/10.1074/jbc.M610701200 PubMedCrossRefGoogle Scholar
  136. Yang YM et al (2009) Alteration of RANKL-induced osteoclastogenesis in primary cultured osteoclasts from SERCA2+/− mice. J Bone Miner Res 24:1763–1769.  https://doi.org/10.1359/jbmr.090420 PubMedCrossRefGoogle Scholar
  137. Yasuda H 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 95:3597–3602PubMedPubMedCentralCrossRefGoogle Scholar
  138. Yasui T, Hirose J, Tsutsumi S, Nakamura K, Aburatani H, Tanaka S (2011) Epigenetic regulation of osteoclast differentiation: possible involvement of Jmjd3 in the histone demethylation of Nfatc1. J Bone Miner Res 26:2665–2671.  https://doi.org/10.1002/jbmr.464 PubMedCrossRefGoogle Scholar
  139. Zachowski A (1993) Phospholipids in animal eukaryotic membranes: transverse asymmetry and movement. Biochem J 294:1–14PubMedPubMedCentralCrossRefGoogle Scholar
  140. Zhao H, Ito Y, Chappel J, Andrews NW, Teitelbaum SL, Ross FP (2008) Synaptotagmin VII regulates bone remodeling by modulating osteoclast and osteoblast secretion. Dev Cell 14:914–925.  https://doi.org/10.1016/j.devcel.2008.03.022 PubMedPubMedCentralCrossRefGoogle Scholar
  141. Zhao B et al (2009) Interferon regulatory factor-8 regulates bone metabolism by suppressing osteoclastogenesis. Nat Med 15:1066–1071.  https://doi.org/10.1038/nm.2007 PubMedPubMedCentralCrossRefGoogle Scholar
  142. Zhao B, Grimes SN, Li S, Hu X, Ivashkiv LB (2012) TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J. J Exp Med 209:319–334.  https://doi.org/10.1084/jem.20111566 PubMedPubMedCentralCrossRefGoogle Scholar
  143. Zou W et al (2007) Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption. J Cell Biol 176:877–888.  https://doi.org/10.1083/jcb.200611083 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Cell Signaling, Graduate School of Medical and Dental SciencesTokyo Medical and Dental University (TMDU)TokyoJapan
  2. 2.Core Research for Evolutional Science and Technology (CREST)Japan Agency for Medical Research and Development (AMED)TokyoJapan

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