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Non-Canonical (RANKL-Independent) Pathways of Osteoclast Differentiation and Their Role in Musculoskeletal Diseases

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Abstract

Osteoclasts are multinucleated cells derived from mononuclear phagocyte precursors (monocytes, macrophages); in the canonical pathway of osteoclastogenesis, these cells fuse and differentiate to form specialised bone-resorbing osteoclasts in the presence of receptor activator for nuclear factor kappa B ligand (RANKL). Non-canonical pathways of osteoclastogenesis have been described in which several cytokines and growth factors are able to substitute for RANKL. These humoral factors can generally be divided into those which, like RANKL, are tumour necrosis family (TNF) superfamily members and those which are not; the former include TNFα lymphotoxin exhibiting inducible expression and competing with herpes simplex virus glycoprotein D for herpesvirus entry mediator, a receptor expressed by T lymphocytes (LIGHT), a proliferation inducing ligand (APRIL) and B cell activating factor (BAFF); the latter include transforming growth factor beta (TGF-β), interleukin-6 (IL-6), IL-8, IL-11, nerve growth factor (NGF), insulin-like growth factor-I (IGF-I) and IGF-II. This review summarises the evidence for these RANKL substitutes in inducing osteoclast differentiation from tissue-derived and circulating mononuclear phagocytes. It also assesses the role these factors are likely to play in promoting the pathological bone resorption seen in many inflammatory and neoplastic lesions of bone and joint including rheumatoid arthritis, aseptic implant loosening and primary and secondary tumours of bone.

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References

  1. Knowles HJ, Athanasou NA (2009) Canonical & non-canonical pathways of osteoclast formation. Histol Histopathol 24:337–346

    CAS  PubMed  Google Scholar 

  2. Athanasou NA (2011) The osteoclast—what’s new? Skelet Radiol 40:1137–1140

    Article  Google Scholar 

  3. Massey HM, Flanagan AM (1999) Human osteoclasts derive from CD14-positive monocytes. Br J Haematol 106:167–170

    Article  CAS  PubMed  Google Scholar 

  4. Fujikawa Y, Quinn JM, Sabokbar A, McGee JO’D, Athanasou NA (1996) The human osteoclast precursor circulates in the monocyte fraction. Endocrinology 137:4058–4060

    CAS  PubMed  Google Scholar 

  5. Walker DG (1993) Bone resorption restored in osteopetrotic mice by transplants of normal bone marrow and spleen cells. Clin Orthop Relat Res 294:4–6

    PubMed  Google Scholar 

  6. Faust J, Lacey DL, Hunt P et al (1999) Osteoclast markers accumulate on cells developing from human peripheral blood mononuclear precursors. J Cell Biochem 72:67–80

    Article  CAS  PubMed  Google Scholar 

  7. Lacey DL, Timms E, Tan HL et al (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176

    Article  CAS  PubMed  Google Scholar 

  8. 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 U S A 95:3597–3602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lum L, Wong BR, Josien R et al (1999) Evidence for a role of a tumour necrosis factor-alpha (TNF-alpha)-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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Kitazawa R, Kitazawa S (2002) Vitamin D(3) augments osteoclastogenesis via vitamin D-responsive element of mouse RANKL gene promoter. Biochem Biophys Res Commun 290:650–655

    Article  CAS  PubMed  Google Scholar 

  12. Horwood NJ, Elliott J, Martin TJ, Gillespie MT (1998) Osteotropic agents regulate the expression of osteoclast differentiation factor and osteoprotegerin in osteoblastic stromal cells. Endocrinology 139:4743–4746

    Article  CAS  PubMed  Google Scholar 

  13. Hofbauer LC, Lacey DL, Dunstan CR, Spelsberg TC, Riggs BL, Khosla S (1999) Interleukin-1beta and tumour necrosis factor-alpha, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone 25:255–259

    Article  CAS  PubMed  Google Scholar 

  14. Atkins GJ, Bouralexis S, Haynes DR et al (2001) Osteoprotegerin inhibits osteoclast formation and bone resorbing activity in giant cell tumors of bone. Bone 28:370–377

    Article  CAS  PubMed  Google Scholar 

  15. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li J, Sarosi I, Yan XQ 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 U S A 97:1566–1571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Khosla S (2001) Minireview: the OPG/RANKL/RANK system. Endocrinology 142:5050–5055

    Article  CAS  PubMed  Google Scholar 

  18. Kim N, Odgren PR, Kim DK, Marks SC Jr, Choi Y (2000) Diverse roles of the tumour necrosis factor family member TRANCE in skeletal physiology revealed by TRANCE deficiency and partial rescue by a lymphocyte-expressed TRANCE transgene. Proc Natl Acad Sci U S A 97:10905–10910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Odgren PR, Kim N, MacKay CA, Mason-Savas A, Choi Y, Marks SC Jr (2003) The role of RANKL (TRANCE/TNFSF11), a tumour necrosis factor family member, in skeletal development: effects of gene knockout and transgenic rescue. Connect Tissue Res 44(Suppl 1):264–271

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Udagawa N, Takahashi N, Yasuda H et al (2000) Osteoprotegerin produced by osteoblasts is an important regulator in osteoclast development and function. Endocrinology 141:3478–3484

    CAS  PubMed  Google Scholar 

  22. Hofbauer LC (1999) Osteoprotegerin ligand and osteoprotegerin: novel implications for osteoclast biology and bone metabolism. Eur J Endocrinol 141:195–210

    Article  CAS  PubMed  Google Scholar 

  23. Mizuno A, Amizuka N, Irie K et al (1998) Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun 247:610–615

    Article  CAS  PubMed  Google Scholar 

  24. Bucay N, Sarosi I, Dunstan CR et al (1998) Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12:1260–1268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wada T, Nakashima T, Hiroshi N, Penninger JM (2006) RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med 2006(12):17–25

    Article  CAS  Google Scholar 

  26. Lomaga MA, Yeh WC, Sarosi I et al (1999) TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signalling. Genes Dev 13:1015–1024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kanazawa K, Kudo A (2000) TRAF2 is essential for TNF-alpha-induced osteoclastogenesis. J Bone Miner Res 20:840–847

    Article  CAS  Google Scholar 

  28. Kanazawa K, Azuma Y, Nakano H, Kudo A (2003) TRAF5 functions in both RANKL- and TNF alpha-induced osteoclastogenesis. J Bone Miner Res 18:443–450

    Article  CAS  PubMed  Google Scholar 

  29. Nakamura I, Takahashi N, Sasaki T et al (1995) A specific inhibitor of phosphatidylinositol-3 kinase, blocks osteoclastic bone resorption. FEBS Lett 361:79–84

    Article  CAS  PubMed  Google Scholar 

  30. Iotsova V, Caamaño J, Loy J, Yang Y, Lewin A, Bravo R (1997) Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Nat Med 3:1285–1289

    Article  CAS  PubMed  Google Scholar 

  31. Soriano P, Montgomery C, Geske R, Bradley A (1991) Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64:693–702

    Article  CAS  PubMed  Google Scholar 

  32. Takeshita S, Namba N, Zhao J et al (2002) SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclasts. Nat Med 8:943–949

    Article  CAS  PubMed  Google Scholar 

  33. 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 115:4317–4325

    Article  CAS  PubMed  Google Scholar 

  34. Kenner L, Hoebertz A, Beil FT et al (2004) Mice lacking JunB are osteopenic due to cell-autonomous osteoblast and osteoclast defects. J Cell Biol 164:613–623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wagner EF (2002) Functions of AP1 (Fos/Jun) in bone development. Ann Rheum Dis 61(Suppl 2):40–42

    Article  Google Scholar 

  36. Fleischmann A, Hafezi F, Elliott C, Remé CE, Rüther U, Wagner EF (2000) Fra-1 replaces c-Fos-dependent functions in mice. Genes Dev 14:2695–2700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Felix R, Hofstetter W, Wetterwald A, Cecchini MG, Fleisch H (1994) Role of colony-stimulating factor-1 in bone metabolism. J Cell Biochem 55:340–349

    Article  CAS  PubMed  Google Scholar 

  38. Flanagan AM, Lader CS (1998) Update on the biologic effects of macrophage colony-stimulating factor. Curr Opin Hematol 5:181–185

    Article  CAS  PubMed  Google Scholar 

  39. Motoyoshi K (1998) Biological activities and clinical application of M-CSF. Int J Hematol 67:109–122

    Article  CAS  PubMed  Google Scholar 

  40. Sherr CJ, Rettenmier CW, Sacca R, Roussel MF, Look AT, Stanley ER (1985) The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1. Cell 41:665–676

    Article  CAS  PubMed  Google Scholar 

  41. Felix R, Cecchini MG, Fleisch H (1990) Macrophage colony stimulating factor restores in vivo bone resorption in the op/op osteopetrotic mouse. Endocrinology 127:2592–2594

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  43. Mabilleau G, Pascaretti-Grizon F, Basle MF, Chappard D (2012) Depth and volume of resorption induced by osteoclasts generated in the presence of RANKL, TNF-alpha/IL-1 or LIGHT. Cytokine 57(2):294–299

    Article  CAS  PubMed  Google Scholar 

  44. Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL (2000) TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest 106:1481–1488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Azuma Y, Kaji K, Katogi R, Takeshita S, Kudo A (2000) Tumour necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts. J Biol Chem 275:4858–4864

    Article  CAS  PubMed  Google Scholar 

  46. Bossen C, Ingold K, Tardivel A et al (2006) Interactions of tumour necrosis factor (TNF) and TNF receptor family members in the mouse and human. J Biol Chem 281:13964–13971

    Article  CAS  PubMed  Google Scholar 

  47. Edwards JR, Sun SG, Locklin R et al (2006) LIGHT (TNFSF14), a novel mediator of bone resorption, is elevated in rheumatoid arthritis. Arthritis Rheum 54:1451–1462

    Article  CAS  PubMed  Google Scholar 

  48. Pasero C, Barbarat B, Just-Landi S et al (2009) A role for HVEM, but not lymphotoxin-beta receptor, in LIGHT-induced tumour cell death and chemokine production. Eur J Immunol 39:2502–2514

    Article  CAS  PubMed  Google Scholar 

  49. Atkins GJ, Haynes DR, Graves SE et al (2000) Expression of osteoclast differentiation signals by stromal elements of giant cell tumors. J Bone Miner Res 15:640–649

    Article  CAS  PubMed  Google Scholar 

  50. Itonaga I, Sabokbar A, Murray DW, Athanasou NA (2000) Effect of osteoprotegerin and osteoprotegerin ligand on osteoclast formation by arthroplasty membrane derived macrophages. Ann Rheum Dis 59:26–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tervahartiala T, Koski H, Xu JW, Häyrinen-Immonen R, Hietanen J, Sorsa T, Konttinen YT (2001) Tumor necrosis factor-alpha and its receptors, p55 and p75, in gingiva of adult periodontitis. J Dent Res 80:1535–1539

    Article  CAS  PubMed  Google Scholar 

  52. Brennan F, McInnes IB (2008) Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest 118:3537–3545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Adamopoulos IE, Sabokbar A, Wordsworth BP, Carr A, Ferguson DJ, Athanasou NA (2006) Synovial fluid macrophages are capable for osteoclast formation and resorption. J Pathol 208:35–43

    Article  CAS  PubMed  Google Scholar 

  54. Chu CQ, Field M, Feldmann M, Maini RN (1991) Localisation of tumour necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis. Arthritis Rheum 34:1125–1132

    Article  CAS  PubMed  Google Scholar 

  55. Shaikh RB, Santee S, Granger SW et al (2001) Constitutive expression of LIGHT on T cells leads to lymphocyte activation, inflammation, and tissue destruction. J Immunol 167:6330–6337

    Article  CAS  PubMed  Google Scholar 

  56. Hohmann EL, Elde RP, Rysavy JA, Einzig S, Gebhard RL (1986) Innervation of periosteum and bone by sympathetic vasoactive intestinal peptide-containing nerve fibers. Science 232:868–871

    Article  CAS  PubMed  Google Scholar 

  57. Wang L, Zhou S, Liu B et al (2006) Locally applied nerve growth factor enhances bone consolidation in a rabbit model of mandibular distraction osteogenesis. J Orthop Res 24:2238–2245

    Article  CAS  PubMed  Google Scholar 

  58. Togari A (2002) Adrenergic regulation of bone metabolism: possible involvement of sympathetic innervation of osteoblastic and osteoclastic cells. Microsc Res Tech 58:77–84

    Article  CAS  PubMed  Google Scholar 

  59. Mohan S, Jennings JC, Linkhart TA, Baylink DJ (1988) Primary structure of human skeletal growth factor: homology with human insulin-like growth factor-II. Biochim Biophys Acta 966:44–55

    Article  CAS  PubMed  Google Scholar 

  60. Hemingway F, Taylor R, Knowles HJ, Athanasou NA (2011) RANKL-independent human osteoclast formation with APRIL, BAFF, NGF, IGF I and IGF II. Bone 48:938–944

    Article  CAS  PubMed  Google Scholar 

  61. Yao Z, Xing L, Boyce BF (2009) NF-kappaB p100 limits TNF-induced bone resorption in mice by a TRAF3-dependent mechanism. J Clin Invest 119:3024–3034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Centrella M, Horowitz MC, Wozney JM, McCarthy TL (1994) Transforming growth factor-gene family members and bone. Endocr Rev 15:27–39

    CAS  PubMed  Google Scholar 

  63. Pfeilschifter J, Seyedin SM, Mundy GR (1998) Transforming growth factor beta inhibits bone resorption in fetal rat long bone culture. J Clin Invest 82:680–685

    Article  Google Scholar 

  64. Inoue M, Ross FP, Erdmann JM, Abu-Amer Y, Wei S, Teitelbaum SL (2006) Tumour necrosis factor alpha regulates alpha(v)beta5 integrin expression by osteoclast precursors in vitro and in vivo. Endocrinology 141:284–290

    Google Scholar 

  65. Kudo O, Fujikawa Y, Itonaga I, Sabokbar A, Torisu T, Athanasou NA (2002) Proinflammatory cytokine (TNFalpha/IL-1alpha) induction of human osteoclast formation. J Pathol 198:220–227

    Article  CAS  PubMed  Google Scholar 

  66. Ma T, Miyanishi K, Suen A et al (2004) Human interleukin-1-induced murine osteoclastogenesis is dependent on RANKL, but independent of TNF-α. Cytokine 26:138–144

    Article  CAS  PubMed  Google Scholar 

  67. Wei S, Kitaura H, Zhou P, Ross FP, Teitelbaum SL (2005) IL-1 mediates TNF-induced osteoclastogenesis. J Clin Invest 115:282–290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Teitelbaum SL (2007) Osteoclasts: what do they do and how do they do it? Am J Pathol 170(2):427–435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Mabilleau G, Chappard D, Sabokbar A (2011) Role of the A20-TRAF6 axis in lipopolysaccharide-mediated osteoclastogenesis. J Biol Chem 286(5):3242–3249

    Article  CAS  PubMed  Google Scholar 

  70. Mahoney DJ, Swales C, Athanasou NA et al (2011) TSG-6 inhibits osteoclast activity via an autocrine mechanism and is functionally synergistic with osteoprotegerin. Arthritis Rheum 63(4):1034–1043

    Article  CAS  PubMed  Google Scholar 

  71. Fuller K, Murphy C, Kirstein B, Fox SW, Chambers TJ (2002) TNFα potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL. Endocrinology 143:1108–1118

    CAS  PubMed  Google Scholar 

  72. Fuller K, Kirstein B, Chambers TJ (2006) Murine osteoclast formation and function: differential regulation by humoral agents. Endocrinology 147:1979–1985

    Article  CAS  PubMed  Google Scholar 

  73. Iqbal J (2006) Does TNF have anti osteoclastogenic actions? Ann N Y Acad Sci 1068:234–239

    Article  CAS  PubMed  Google Scholar 

  74. Mauri DN, Ebner R, Montgomery RI et al (1998) LIGHT, a new member of the TNF superfamily, and lymphotoxin are ligands for herpesvirus entry mediator. Immunity 8:21–30

    Article  CAS  PubMed  Google Scholar 

  75. Tamada K, Shimozaki K, Chapoval AI et al (2000) LIGHT, a TNF-like molecule, costimulates T cell proliferation and is required for dendritic cell-mediated allogeneic T cell response. J Immunol 164:4105–4110

    Article  CAS  PubMed  Google Scholar 

  76. Montgomery RI, Warner MS, Lum BJ, Spear PG (1996) Herpes simplex virus-1 entry into cells mediated by a novel member of TNF/NGF receptor family. Cell 87:427–436

    Article  CAS  PubMed  Google Scholar 

  77. Zhai Y, Guo R, Hsu TL et al (1998) LIGHT, a novel ligand for lymphotoxin receptor and TR2/HVEM, induces apoptosis and suppresses in vivo tumor formation via gene transfer. J Clin Invest 102:1142–1151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Heo SK, Yun HJ, Park WH, Park SD (2008) NADPH oxidase activation is required for migration by LIGHT in human monocytes. Biochem Biophys Res Commun 371:834–840

    Article  CAS  PubMed  Google Scholar 

  79. Schneider K, Potter KG, Ware CF (2004) Lymphotoxin and LIGHT signaling pathways and target genes. Immunol Rev 202:49–66

    Article  CAS  PubMed  Google Scholar 

  80. Chang TH, Hsieh SL, Chao Y, Chou YC, Lin WW (2005) Proinflammatory effects of LIGHT through HVEM and LTbetaR interactions in cultured human umbilical vein endothelial cells. J Biomed Sci 12:363–375

    Article  CAS  PubMed  Google Scholar 

  81. Kang YM, Kim SY, Kang JH et al (2007) LIGHT up-regulated on B lymphocytes and monocytes in rheumatoid arthritis mediates cellular adhesion and metalloproteinase production by synoviocytes. Arthritis Rheum 56:1106–1117

    Article  CAS  PubMed  Google Scholar 

  82. Ye Q, Fraser CC, Gao W et al (2002) Modulation of LIGHT-HVEM costimulation prolongs cardiac allograft survival. J Exp Med 195:795–800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Rooney IA, Butrovich KD, Glass AA et al (2000) The lymphotoxin-beta receptor is necessary and sufficient for LIGHT-mediated apoptosis of tumor cells. J Biol Chem 275:14307–14315

    Article  CAS  PubMed  Google Scholar 

  84. Granger SW, Rickert S (2003) LIGHT-HVEM signaling and the regulation of T cell-mediated immunity. Cytokine Growth Factor Rev 14:289–296

    Article  CAS  PubMed  Google Scholar 

  85. Marsters SA, Ayres TM, Skubatch M, Gray CL, Rothe M, Ashkenazi A (1997) Herpesvirus entry mediator, a member of the tumor necrosis factor receptor (TNFR) family, interacts with members of the TNFR-associated factor family and activates the transcription factors NF-kappaB and AP-1. J Biol Chem 272:14029–14032

    Article  CAS  PubMed  Google Scholar 

  86. Yang CR, Wang JH, Hsieh SL, Wang SM, Hsu TL, Lin WW (2004) Decoy receptor 3 (DcR3) induces osteoclast formation from monocyte/macrophage lineage precursor cells. Cell Death Differ. Suppl 1:S97-107

  87. Hemingway F, Kashima TG, Knowles HJ, Athanasou NA (2013) Investigation of osteoclastogenic signalling of the RANKL substitute LIGHT. Exp Mol Pathol 94:380–385

    Article  CAS  PubMed  Google Scholar 

  88. Arch RH, Gedrich RW, Thompson CB (1998) Tumour necrosis factor receptor-associated factors (TRAFs) - a family of adapter proteins that regulates life and death. Genes Dev 12:2821–2830

    Article  CAS  PubMed  Google Scholar 

  89. Hahne M, Kataoka T, Schroter M et al (1998) APRIL, a new ligand of the tumor necrosis factor family, stimulates tumor cell growth. J Exp Med 188:1185–1190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Kelly K, Manos E, Jensen G, Nadauld L, Jones DA (2000) APRIL/TRDL-1, a tumor necrosis factor-like ligand, stimulates cell death. Cancer Res 60:1021–1027

    CAS  PubMed  Google Scholar 

  91. Schneider P, MacKay F, Steiner V et al (1999) BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med 189:1747–1756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Bonewald LF (1995) Regulation and regulatory activities of transforming growth factor beta. Crit Rev Eukaryot Gene Exp 9:33–44

    Google Scholar 

  93. Massey HM, Scopes J, Horton MA, Flanagan AM (2002) Transforming growth factor-beta stimulates the osteoclast-forming potential of peripheral blood haematopoietic precursors in a lymphocyte-rich microenvironment. Bone 28:577–582

    Article  Google Scholar 

  94. Beaudreuil J, Mbalaviele G, Cohen-Solal M, Morieux C, de Vernejoul MC, Orcel P (1995) Short-term local injections of transforming growth factor-beta 1 decrease ovariectomy-stimulated osteoclastic resorption in vivo in rat. J Bone Miner Res 10:971–977

    Article  CAS  PubMed  Google Scholar 

  95. Ota K, Quint P, Weivoda MM et al (2013) Transforming growth factor beta 1 induces CXCL16 and leukemia inhibitory factor expression in osteoclasts to modulate migration of osteoblast progenitors. Bone 57:68–75

    Article  CAS  PubMed  Google Scholar 

  96. Itonaga I, Sabokbar A, Sun SG et al (2004) Transforming growth factor-beta induces osteoclast formation in the absence of RANKL. Bone 34:57–64

    Article  CAS  PubMed  Google Scholar 

  97. Takai H, Kanematsu M, Yano K et al (1998) Transforming growth factor-beta stimulates the production of osteoprotegerin/osteoclastogenesis inhibitory factor by bone marrow stromal cells. J Biol Chem 273:27091–27096

    Article  CAS  PubMed  Google Scholar 

  98. Ishimi Y, Miyaura C, Jin CH et al (1990) IL-6 is produced by osteoblasts and induces bone resorption. J Immunol 145:3297–3303

    CAS  PubMed  Google Scholar 

  99. Tamura T, Udagawa N, Takahashi N et al (1993) Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc Natl Acad Sci U S A 90:11924–11928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kudo O, Sabokbar A, Pocock A, Itonaga I, Fujikawa Y, Athanasou NA (2003) Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism. Bone 32:1–7

    Article  CAS  PubMed  Google Scholar 

  101. Roodman GD, Kurihara N, Ohsaki Y et al (1992) Interleukin 6. A potential autocrine/paracrine factor in Paget’s disease of bone. J Clin Invest 89:46–52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Bendre MS, Montague DC, Peery T, Akel NS, Gaddy D, Suva LJ (2003) Interleukin-8 stimulation of osteoclastogenesis and bone resorption is a mechanism for the increased osteolysis of metastatic bone disease. Bone 33:28–37

    Article  CAS  PubMed  Google Scholar 

  103. Bendre MS, Margulies AG, Walser B et al (2005) Tumour-derived interleukin-8 stimulates osteolysis independent of the receptor activator of nuclear factor-kappaB ligand pathway. Cancer Res 65:11001–11009

    Article  CAS  PubMed  Google Scholar 

  104. Asaumi K, Nakanishi T, Asahara H, Inoue H, Takigawa M (2000) Expression of neurotrophins and their receptors (TRK) during fracture healing. Bone 26:625–633

    Article  CAS  PubMed  Google Scholar 

  105. Frenkel SR, Guerra LA, Mitchell OG, Singh IJ (1990) Nerve growth factor in skeletal tissues of the embryonic chick. Cell Tissue Res 260:507–511

    Article  CAS  PubMed  Google Scholar 

  106. Grills B, Schuijers J (1998) Immunohistochemical localization of nerve growth factor in fractured and unfractured rat bone. Acta Orthop Scand 69:415–419

    Article  CAS  PubMed  Google Scholar 

  107. Hukkanen M, Konttinen Y, Santavirta S et al (1993) Rapid proliferation of calcitonin gene-related peptide-immunoreactive nerves during healing of rat tibial fracture suggests neural involvement in bone growth and remodelling. Neuroscience 54:969–979

    Article  CAS  PubMed  Google Scholar 

  108. Serre CM, Farlay D, Delmas PD, Chenu C (1990) Evidence for a dense and intimate innervation of the bone tissue, including glutamate-containing fibers. Bone 25:623–629

    Article  Google Scholar 

  109. Bautista CM, Mohan S, Baylink DJ (1990) Insulin-like growth factors I and II are present in the skeletal tissues of ten vertebrates. Metabolism 39:96–100

    Article  CAS  PubMed  Google Scholar 

  110. Hayden JM, Mohan S, Baylink DJ (1995) The insulin-like growth factor system and the coupling of formation to resorption. Bone 17:93S–98S

    Article  CAS  PubMed  Google Scholar 

  111. Hill PA, Reynolds JJ, Meikle MC (1995) Osteoblasts mediate insulin-like growth factor-I and -II stimulation of osteoclast formation and function. Endocrinology 136:124–131

    CAS  PubMed  Google Scholar 

  112. Fukuoka H, Aoyama M, Miyazawa K, Asai K, Goto S (2005) Hypoxic stress enhances osteoclast differentiation via increasing IGF2 production by non-osteoclastic cells. Biochem Biophys Res Commun 328:885–894

    Article  CAS  PubMed  Google Scholar 

  113. Mochizuki H, Hakeda Y, Wakatsuki N et al (1992) Insulin-like growth factor-I supports formation and activation of osteoclasts. Endocrinology 131:1075–1080

    CAS  PubMed  Google Scholar 

  114. Nakao K, Aoyama M, Fukuoka H, Fujita M, Miyazawa K, Asai K, Goto S (2009) IGF II modulates the microenvironment for osteoclastogenesis. Biochem Biophys Res Commun 378:462–466

    Article  CAS  PubMed  Google Scholar 

  115. Zhang M, Xuan S, Bouxsein ML et al (2002) Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signalling in bone matrix mineralization. J Biol Chem 277:44005–44012

    Article  CAS  PubMed  Google Scholar 

  116. Wang Y, Nishida S, Elalieh HZ, Long RK, Halloran BP, Bikle DD (2006) Role of IGF-I signaling in regulating osteoclastogenesis. J Bone Miner Res 21:1350–1358

    Article  CAS  PubMed  Google Scholar 

  117. Guicheux J, Heymann D, Rousselle AV et al (1998) Growth hormone stimulatory effects on osteoclastic resorption are partly mediated by insulin-like growth factor I: an in vitro study. Bone 22:25–31

    Article  CAS  PubMed  Google Scholar 

  118. Bautista CM, Baylink DJ, Mohan S (1991) Isolation of a novel insulin-like growth factor (IGF) binding protein from human bone: a potential candidate for fixing IGF-II in human bone. Biochem Biophys Res Commun 176:756–763

    Article  CAS  PubMed  Google Scholar 

  119. Middleton J, Arnott N, Walsh S, Beresford J (1995) Osteoblasts and osteoclasts in adult human osteophyte tissue express the mRNAs for insulin-like growth factors I and II and the type 1 IGF receptor. Bone 16:287–293

    Article  CAS  PubMed  Google Scholar 

  120. Zheng MH, Fan Y, Smith A, Wysocki S, Papadimitriou JM, Wood DJ (1998) Gene expression of monocyte chemoattractant protein-1 in giant cell tumors of bone osteoclastoma: possible involvement in CD68+ macrophage-like cell migration. J Cell Biochem 70:121–129

    Article  CAS  PubMed  Google Scholar 

  121. Franchi A, Benvenuti S, Masi L et al (2001) TGF-beta isoform and receptor expression in giant cell tumor and giant cell lesions of bone. Appl Immunohistochem Mol Morphol 9:170–175

    CAS  PubMed  Google Scholar 

  122. Middleton J, Arnott N, Walsh S, Beresford J (1996) The expression of mRNA for insulin-like growth factors and their receptor in giant cell tumors of human bone. Clin Orthop 322:224–231

    Article  PubMed  Google Scholar 

  123. Mhawech-Fauceglia P, Kaya G, Sauter G et al (2006) The source of APRIL up-regulation in human solid tumor lesions. J Leukoc Biol 80:697–704

    Article  CAS  PubMed  Google Scholar 

  124. Lau YS, Adamopoulos IE, Sabokbar A, Giele H, Gibbons CL, Athanasou NA (2007) Cellular and humoral mechanisms of osteoclast formation in Ewing’s sarcoma. Br J Cancer 96:1716–1722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Lau YS, Danks L, Sun SG et al (2007) RANKL-dependent and RANKL-independent mechanisms of macrophage-osteoclast differentiation in breast cancer. Breast Cancer Res Treat 105:7–16

    Article  CAS  PubMed  Google Scholar 

  126. Lau YS, Sabokbar A, Giele H, Cerundolo V, Hofstetter W, Athanasou NA (2006) Malignant melanoma and bone resorption. Br J Cancer 94(10):1496–1503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Oranger A, Carbone C, Izzo M, Grano M. (2013) Cellular mechanisms of multiple myeloma bone disease. Clin Dev Immunol. 289458

  128. Brunetti G, Rizzi R, Oranger A et al (2014) LIGHT/TNFSF14 increases osteoclastogenesis and decreases osteoblastogenesis in multiple myeloma-bone disease. Oncotarget 5:12950–12967

    Article  PubMed  PubMed Central  Google Scholar 

  129. Galson DL, Roodman GD (2014) Pathobiology of Paget’s Disease of Bone. J Bone Metab 21:85–98

    Article  PubMed  PubMed Central  Google Scholar 

  130. Hirayama T, Sabokbar A, Itonaga I, Watt-Smith S, Athanasou NA (2014) Cellular and humoral mechanisms of osteoclast formation and bone resorption in Gorham-Stout disease. J Pathol 195:624–630

    Article  CAS  Google Scholar 

  131. Neri P, Kumar S, Fulciniti MT et al (2007) Neutralizing B-cell activating factor antibody improves survival and inhibits osteoclastogenesis in a severe combined immunodeficient human multiple myeloma model. Clin Cancer Res 13:5903–5909

    Article  CAS  PubMed  Google Scholar 

  132. Moreaux J, Cremer FW, Reme T et al (2005) The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature. Blood 106:1021–1030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Abe M, Kido S, Hiasa M et al (2006) BAFF and APRIL as osteoclast-derived survival factors for myeloma cells: a rationale for TACI-Fc treatment in patients with multiple myeloma. Leukemia 20:1313–1315

    Article  CAS  PubMed  Google Scholar 

  134. Sabokbar A, Kudo O, Athanasou NA (2003) Two distinct cellular mechanisms of osteoclast formation and bone resorption in periprosthetic osteolysis. J Orthop Res 21:73–80

    Article  CAS  PubMed  Google Scholar 

  135. Yang YM, Kim SY, Kang JH et al (2007) LIGHT up regulated on B lymphocytes and monocytes in rheumatoid arthritis mediates cellular adhesion and metalloproteinase production by synoviocytes. Arthritis Rheum 56:1106–1107

    Article  CAS  Google Scholar 

  136. Fava RA, Notidis E, Hunt J et al (2003) A role for the lymphotoxin/LIGHT axis in the pathogenesis of murine collagen-induced arthritis. J Immunol 171:115–116

    Article  CAS  PubMed  Google Scholar 

  137. Ishida S, Yamane S, Nakano S et al (2009) The interaction of monocytes with rheumatoid synovial cells is a key step in LIGHT-mediated inflammatory bone destruction. Immunology 128:315–324

    Article  Google Scholar 

  138. Ishida S, Yamane S, Ochi T et al (2003) LIGHT induces cell proliferation and inflammatory responses of rheumatoid arthritis synovial fibroblasts via lymphotoxin beta receptor. J Rheumatol 35:960–968

    Google Scholar 

  139. Pierer M, Brentano F, Rethage J. et al. (2009) The TNF superfamily member LIGHT contributes to survival and activation of synovial fibroblasts in rheumatoid arthritis

  140. Cheung TC, Coppieters K, Sanjo H et al (2010) Polymorphic variants of LIGHT (TNF superfamily −14) alter receptor avidity and bioavailability. J Immunol 185:1949–1958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Mariette X, Roux S, Zhang J et al (2003) The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjogren’s syndrome. Ann Rheum Dis 62:168–171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Pers JO, Daridon C, Devauchelle V et al (2005) BAFF overexpression is associated with autoantibody production in autoimmune diseases. Ann N Y Acad Sci 1050:34–39

    Article  CAS  PubMed  Google Scholar 

  143. Dickerson TJ, Suzuki E, Stanecki C, Shin HS, Qui H, Adamopoulos IE (2012) Rheumatoid and pyrophosphate arthritis synovial fibroblasts induce osteoclastogenesis independently of RANKL, TNF and IL-6. J Autoimmun 39:369–376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Adamopoulos IE, Tessmer M, Chao CC et al (2011) IL-23 is critical for induction of arthritis, osteoclast formation, and maintenance of bone mass. J Immunol 187:951–959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Adamopoulos IE, Mellins ED (2015) Alternative pathways of osteoclastogenesis in inflammatory arthritis. Nat Rev Rheumatol 11:189–194

    Article  CAS  PubMed  Google Scholar 

  146. Shin HS, Sarin R, Dixit N, Wu J, Gershwin E, Bowman EP, Adamopoulos IE (2015) Crosstalk among IL-23 and DNAX activating protein of 12 kDa-dependent pathways promotes osteoclastogenesis. J Immunol 194:316–324

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We would like to thank Sarah Turton for typing the manuscript. NAA and AS are supported by the Oxford NIHR BRU, The Rosetrees Trust, Sarcoma (UK) and the Bone Cancer Research Trust.

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  1. The Botnar Research Centre, Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal and Clinical Laboratory Services, Nuffield Orthopaedic Centre, University of Oxford, Oxford, OX3 7LD, UK

    A. Sabokbar, D. J. Mahoney, F. Hemingway & N. A. Athanasou

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  1. A. Sabokbar
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  2. D. J. Mahoney
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  4. N. A. Athanasou
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Correspondence to N. A. Athanasou.

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Afsie Sabokbar, David Mahoney, Francesca Hemingway and Nicholas Athanasou declare that they have no conflict of interest.

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Sabokbar, A., Mahoney, D.J., Hemingway, F. et al. Non-Canonical (RANKL-Independent) Pathways of Osteoclast Differentiation and Their Role in Musculoskeletal Diseases. Clinic Rev Allerg Immunol 51, 16–26 (2016). https://doi.org/10.1007/s12016-015-8523-6

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