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Pathophysiology of Bone Disease in Multiple Myeloma

  • Tomer M. Mark
  • Roger N. Pearse
Part of the Contemporary Hematology book series (CH)

Introduction

Multiple myeloma (MM) is a malignancy of plasma cells characterized by growth in the bone marrow (BM) environment and the development of lytic lesions in the skeleton. These lytic lesions are responsible for many of the clinical sequelae of progressive disease, including pathologic fractures, severe pain, and hypercalcemia.1 Historically, the burden of skeletal disease has been used to predict MM prognosis and survival, as outlined in the Salmon-Durie staging system.2 However, this correlation is weakened by the finding of increased prevalence of bone disease in MM with favorable cytogenetics.3 As a result, bone disease has been omitted from recent staging schema.4 Nonetheless, bone destruction remains a major source of morbidity.5

The hallmark of MM bone disease is the development of osteolytic lesions without associated osteoblastic activity. The absence of reactive bone formation renders MM-associated skeletal lesions silent on bone scan, and helps to explain the...

Keywords

Multiple Myeloma Bone Marrow Stromal Cell Bone Destruction Adenomatous Polyposis Coli Gene Bone Marrow Plasma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Bataille R, Harousseau JL. MM. N Engl J Med 1997; 336:1657–1664.PubMedCrossRefGoogle Scholar
  2. 2.
    Durie BG, Salmon SE. Cellular kinetics, staging, and immunoglobulin synthesis in MM. Annu Rev Med 1975; 26:283–288.PubMedCrossRefGoogle Scholar
  3. 3.
    Robbiani D, Chesi M, Bergsagel PL. Bone lesions in molecular subtypes of MM. N Engl J Med 2004; 351:197–198.PubMedCrossRefGoogle Scholar
  4. 4.
    Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol 2005; 23(15):3412–3420.PubMedCrossRefGoogle Scholar
  5. 5.
    Lane JM, Hong R, Koob J, et al. Kyphoplasty enhances function and structural alignment in multiple myeloma Clin Orthop Relat Res 2004; 426:49–53.PubMedCrossRefGoogle Scholar
  6. 6.
    Pearse R. Wnt antagonism in MM: A potential cause of uncoupled bone remodeling. Clin Cancer Res 2006; 12 (20 Suppl):6274s–6278s.PubMedCrossRefGoogle Scholar
  7. 7.
    Roodman GD. Regulation of osteoclast differentiation. Ann N Y Acad Sci 2006; 1068:100–109.PubMedCrossRefGoogle Scholar
  8. 8.
    Hadkidakis D, Androulakis I. Bone remodeling. Ann N Y Acad Sci 2006; 1092:385–396.CrossRefGoogle Scholar
  9. 9.
    Niida S, Kaku M, Amano H, et al. Vascular endothelial growth factor can substitute for macrophage colony-stimulating factor in the support of osteoclastic bone resorption. J Exp Med 1999; 190:293–298.PubMedCrossRefGoogle Scholar
  10. 10.
    Dai XM, Ryan GR, Hapel AJ, et al. Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood 2002; 99(1):111–120.PubMedCrossRefGoogle Scholar
  11. 11.
    Han JH, Choi SJ, Kurihara N. Macrophage inflammatory protein-1 alpha is an osteoclastogenic factor in MM that is independent of receptor activator of nuclear factor kappa B ligand. Blood 2001; 97:3349–3353.PubMedCrossRefGoogle Scholar
  12. 12.
    Tolar J, Teitelbaum SL, Orchard PJ. Osteopetrosis. N Engl J Med 2004; 351:2839–2849.PubMedCrossRefGoogle Scholar
  13. 13.
    Hsu H, Lacey DL, Dunstan CR, et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteopro-tegerin ligand. Proc Natl Acad Sci 1999; 96:3540–3545.PubMedCrossRefGoogle Scholar
  14. 14.
    Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003; 423(6937):337–342.PubMedCrossRefGoogle Scholar
  15. 15.
    Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998; 93:165–176.PubMedCrossRefGoogle Scholar
  16. 16.
    Heider U, Hofbauer LC, Zacriski I, et al. Novel aspects of osteoclast activation and OBL inhibition in MM bone Biochem Biophys Res Commun 2005; 338:687–693.PubMedCrossRefGoogle Scholar
  17. 17.
    Roodman GD. Mechanisms of disease: mechanisms of bone metastasis. N Engl J Med 2004; 350:1655–1664.PubMedCrossRefGoogle Scholar
  18. 18.
    Roodman GD, et al. Interleukin 6. A potential autocrine/paracrine factor in Paget's disease of bone J Clin Invest 1992; 89:46–52.PubMedCrossRefGoogle Scholar
  19. 19.
    Teitelbaum SL. Bone resorption by osteoclasts Science 2000; 289:1504–1508.PubMedCrossRefGoogle Scholar
  20. 20.
    Odgren PR, Kim N, MacKay CA, et al. The role of RANKL (TRANCE/TNFSF11), a tumor necrosis factor family member, in skeletal development: effects of gene knockout and transgenic rescue Connect Tissue Res 2003; 44 Suppl 1:264–271.PubMedGoogle Scholar
  21. 21.
    Wong BR, Josien R, Lee SY, et al. The TRAF family of signal transducers mediates NF-kappaB activation by the TRANCE receptor. J Biol Chem 1998; 273(43):28355–28359.PubMedCrossRefGoogle Scholar
  22. 22.
    Xing L, et al. NF-kappaB p50 and p52 expression is not required for RANK-expressing osteoclast progenitor formation but is essential for RANK- and cytokine-mediated osteoclastogenesis J Bone Miner Res 2002; 17:1200–1210.PubMedCrossRefGoogle Scholar
  23. 23.
    Asagiri M, Takayanagi H. The molecular understanding of osteoclast differentiation. Bone 2007; 40(2):251–264.PubMedCrossRefGoogle Scholar
  24. 24.
    Mansky KC, Sankar U, Han J, et al. Microphthalmia transcription factor is a target of the p38 MAPK pathway in response to receptor activator of NF-kappa B ligand signaling. J Biol Chem 2002; 277(13):11077–11083.PubMedCrossRefGoogle Scholar
  25. 25.
    Dougall WC, Glaccum M, Charrier K, et al. RANK is essential for osteoclast and lymph node development. Genes Dev 1999; 13(18):2412–2424.PubMedCrossRefGoogle Scholar
  26. 26.
    Teitelbaum SL. Bone resorption by osteoclasts Science 2000; 289:1504–1508.PubMedCrossRefGoogle Scholar
  27. 27.
    Terpos E, Politou M, Rahemtulla A. New insights into the pathophysiology and management of bone disease in MM Br J Haematol 2003; 123:758–769.PubMedCrossRefGoogle Scholar
  28. 28.
    Kong YY, Yoshida H, Sarosi I, et al. OPGL is a key regulator of osteoclastogen-esis, lymphocyte development, and lymph-node organogenesis.Nature 1999; 397: 315–323.PubMedCrossRefGoogle Scholar
  29. 29.
    Bucay N, Sarosi I, Dunstan CR. Osteoprotegerin-deficient mice develop early-onset osteoporosis and arterial calcification.Genes Dev 1998; 12:1260–1268.PubMedCrossRefGoogle Scholar
  30. 30.
    Robey PG, Young MF, Flanders KC, et al. Osteoblasts synthesize and respond to transforming growth factor-type beta (TGF-beta) in vitro J Cell Biol 1987; 105(1):457–463.PubMedCrossRefGoogle Scholar
  31. 31.
    Bonewald LF, Dallas SL. Role of active and latent transforming growth factor beta in bone formation J Cell Biochem 1994; 55(3):350–357.PubMedCrossRefGoogle Scholar
  32. 32.
    Janssens K, ten Dijke P, Janssens S, et al. Transforming growth factor-beta1 to the bone. Endocr Rev 2005; 26(6):743–774.PubMedCrossRefGoogle Scholar
  33. 33.
    Takayanagi H, Ogasawara K, Hida S, et al. T-cell-mediated regulation of osteoclas-togenesis by signaling cross-talk between RANKL and IFN-gamma. Nature 2000; 408(6812):600–605.PubMedCrossRefGoogle Scholar
  34. 34.
    Zhou Z, Imme lD, Xi CX, et al. Regulation of osteoclast function and bone mass by RAGE. J Exp Med 2006; 203(4):1067–1080.PubMedCrossRefGoogle Scholar
  35. 35.
    Kim N, Takami M, Rho J, et al. A novel member of the leukocyte receptor complex regulates osteoclast differentiation. J Exp Med 2002; 195(2):201–209.PubMedGoogle Scholar
  36. 36.
    Cella M, Buonsanti C, Strader C, et al. Impaired differentiation of osteoclasts in TREM-2-deficient individuals. J Exp Med 2003; 198(4):645–651.PubMedCrossRefGoogle Scholar
  37. 37.
    Koga T, Inui M, Inoue K, et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis Nature 2004; 428(6984):758–763.PubMedCrossRefGoogle Scholar
  38. 38.
    Pearse RN, Sordillo EM, Yaccoby S, et al. MM disrupts the TRANCE/osteopro-tegerin cytokine axis to trigger bone destruction and promote tumor progression. Proc Natl Acad Sci 2001; 98(20):11581–11586.PubMedCrossRefGoogle Scholar
  39. 39.
    Lam J, Takeshita S, Barker JE, et al. TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest 2000; 106(12):1481–1488.PubMedCrossRefGoogle Scholar
  40. 40.
    Taichman RS, Emerson SG. The role of osteoblasts in the hematopoietic microen-vironment. Stem Cells 1998; 16(1):7–15.PubMedCrossRefGoogle Scholar
  41. 41.
    Zhang J, Niu C, Ye L, Huang H, et al. Identification of the haematopoietic stem cell niche and control of the niche size Nature 2003; 425(6960):836–841.PubMedCrossRefGoogle Scholar
  42. 42.
    Calvi LM, Adams GB, Weibrecht KW, et al. Osteoblastic cells regulate the haematopoietic stem cell niche Nature 2003; 425(6960):841–846.PubMedCrossRefGoogle Scholar
  43. 43.
    Ducy P, Zhang R, Geoffroy V, et al. Osf2/Cbfa1: a transcriptional activator of OBL differentiation. Cell 1997; 89:747–754.PubMedCrossRefGoogle Scholar
  44. 44.
    Komori T, Yagi H, Nomura S, et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of OBL Cell 1997; 89:755–764.PubMedCrossRefGoogle Scholar
  45. 45.
    Hu H, Hilton MJ, Tu X, et al. Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development 2005; 132(1):49–60.PubMedCrossRefGoogle Scholar
  46. 46.
    Gong Y, Slee RB, Fukai N, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 2001; 107:513–523.PubMedCrossRefGoogle Scholar
  47. 47.
    Boyden LM, Mao J, Belsky J, et al. High bone density due to a mutation in LDL-receptor-related protein 5 N Engl J Med 2002; 346:1513–1521.PubMedCrossRefGoogle Scholar
  48. 48.
    Rawadi G, Vayssière B, Dunn F, et al. BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop. J Bone Miner Res 2003; 18(10):1842–1853.PubMedCrossRefGoogle Scholar
  49. 49.
    Kato M, Patel MS, Levasseur R, et al. Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in LRP5, a Wnt coreceptor. J Cell Biol 2002; 157(2):303–314.PubMedCrossRefGoogle Scholar
  50. 50.
    Day TF, Guo X, Garrett-Beal L, et al. Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis Dev Cell 2005; 8(5):739–750.PubMedCrossRefGoogle Scholar
  51. 51.
    Hill TP, Später D, Taketo MM, et al. Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell 2005; 8(5):727–738.PubMedCrossRefGoogle Scholar
  52. 52.
    Westendorf JJ, Kahler RA, Schroeder TM. Wnt signaling in OBL and bone diseases. Gene 2004; 341:19–39.PubMedCrossRefGoogle Scholar
  53. 53.
    Franz-Odendaal TA, Hall BK, Witten PE. Buried alive: how osteoblasts become osteocytes Dev Dyn 2006; 235(1):176–190.CrossRefGoogle Scholar
  54. 54.
    Knothe Tate ML, Adamson JR, Tami AE, et al. The osteocyte. Int J Biochem Cell Biol 2004; 36(1):1–8.CrossRefGoogle Scholar
  55. 55.
    Rodan GA, Martin TJ. Role of osteoblasts in hormonal control of bone resorption — a hypothesis. Calcif Tissue Int 1981; 33(4):349–351.PubMedCrossRefGoogle Scholar
  56. 56.
    Zhao C, Irie N, Takada Y, et al. Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis Cell Metab 2006; 4(2):111–121.PubMedCrossRefGoogle Scholar
  57. 57.
    Hayden JM, Mohan S, Baylink DJ. The insulin-like growth factor system and the coupling of formation to resorption Bone 1995; 17(2 Suppl):93S–98S.PubMedCrossRefGoogle Scholar
  58. 58.
    Pfeilschifter J, Mundy GR. Modulation of type beta transforming growth factor activity in bone cultures by osteotropic hormones Proc Natl Acad Sci USA. 1987; 84(7):2024–2028.PubMedCrossRefGoogle Scholar
  59. 59.
    Sheu TJ, Schwarz EM, Martinez DA, et al. A phage display technique identifies a novel regulator of cell differentiation. J Biol Chem 2003; 278(1):438–443.PubMedCrossRefGoogle Scholar
  60. 60.
    Udagawa N, Takahashi N, Jimi E, et al. OBL/stromal cells stimulate osteoclast activation through expression of osteoclast differentiation factor/RANKL but not macrophage colony-stimulating factor: receptor activator of NF-kappa B ligand. Bone 1999; 25(5):517–523.PubMedCrossRefGoogle Scholar
  61. 61.
    Glass D, Bialek P, Karsenty G, et al. Canonical Wnt signaling in differentiated OBL controls ostelast differentiation. Dev Cell 2005; 8:751–764.PubMedCrossRefGoogle Scholar
  62. 62.
    Holmen SL, Zylstra CR, Mukherjee A, et al. Essential role of -catenin in postnatal bone acquisition J Biol Chem 2005; 280:21162–21168.PubMedCrossRefGoogle Scholar
  63. 63.
    Bataille R, Chappard D, Marcelli C, et al. OBL stimulation in MM lacking lytic bone lesions Br J Haematol 1990; 76:484–487.PubMedCrossRefGoogle Scholar
  64. 64.
    Abildgaard N, Brixen K, Eriksen EF, et al. Sequential analysis of biochemical markers of bone resorption and bone densitometry in MM Haematologica 2004; 89(5):567–577.PubMedGoogle Scholar
  65. 65.
    Taube T, Beneton MN, McCloskey EV, et al. Abnormal bone remodeling in patients with myelomatosis and normal biochemical indices of bone resporption. Eur J Haematol 1992; 49:192–198.PubMedCrossRefGoogle Scholar
  66. 66.
    Fonseca R, Trendle MC, Leong T, et al. Prognostic value of serum markers of bone metabolism in untreated MM patients Br J Haematol 2000; 109:24–29.PubMedCrossRefGoogle Scholar
  67. 67.
    Terpos E, Politou M, Rahemtulla A. The role of markers of bone remodeling in MM. Blood Rev 2005; 19(3):125–142.PubMedCrossRefGoogle Scholar
  68. 68.
    Heider U, Hofbauer L, ZavrskiI, et al. Novel aspects of osteoclast activation and OBL inhibition in MM bone disease Biochem Biophys Res Commun 2005; 338:1–7.CrossRefGoogle Scholar
  69. 69.
    Sezer O, Heider U, Jakob C, et al. Immunohistochemistry reveals RANKL expression of MMC Blood 2002; 99:4646–4647.PubMedCrossRefGoogle Scholar
  70. 70.
    Lai FP, Cole-Sinclair M, Cheng WJ. MMC can directly contribute to the pool of RANKL in bone bypassing the classic stromal and osteoblast pathway of osteoclast stimulation. Br J Haematol 2004; 126:192–201.PubMedCrossRefGoogle Scholar
  71. 71.
    Standal T, Seidel C, Hjertner O, et al. Osteoprotegerin is bound, internalized, and degraded by MMC Blood 2002; 100:3002–3007.PubMedCrossRefGoogle Scholar
  72. 72.
    Giuliani N, Bataille R, Mancini C, et al. Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment. Blood 2001; 98(13):3527–3533.PubMedCrossRefGoogle Scholar
  73. 73.
    Cook DC. The role of MIP-1 alpha in inflammation and hematopoeisis. J Leukoc Biol 1996; 59:61–66.PubMedGoogle Scholar
  74. 74.
    Choi S, Cruz JC, Craig F, et al. Macrophage inflammatory protein-1α (MIP-1α) is a potential osteoclast stimulatory factor in MM Blood 2000; 96:671–675.PubMedGoogle Scholar
  75. 75.
    Hashimoto T, Abe M, Oshima T, et al. Ability of MMC to secrete macrophage inflammatory protein (MIP)-1alpha and MIP-1beta correlates with lytic bone lesions in patients with MM Br J Haematol 2004; 125(1):38–41.PubMedCrossRefGoogle Scholar
  76. 76.
    Abe M, Hiura J, Wilde K, et al. Role for macrophage inflammatory protein (MIP)-1 alpha and MIP-1 beta in the development of osteolytic lesions in MM Blood 2002; 100:2195–2202.PubMedGoogle Scholar
  77. 77.
    Choi SJ, Oba Y, Gazitt Y et al. Antisense inhibition of macrophage inflammatory protein 1-alpha blks bone destruction in a model of MM bone disease J Clin Invest 2001; 108:1833–1841.PubMedGoogle Scholar
  78. 78.
    Han J, Choi S, Kurihara N, et al. Macrophage inflammatory protein-1 is an osteo-clastogenic factor in MM that is independent of receptor activator of nuclear B ligand. Blood 2001; 97:3349–3353.PubMedCrossRefGoogle Scholar
  79. 79.
    Lentzsch S, Gries M, Janz R, et al. Macrophage inflammatory protein-1 alpha triggers migration and signaling cascades mediating survival and proliferation in MM cells. Blood 2003; 101:3568–3573.PubMedCrossRefGoogle Scholar
  80. 80.
    Menu E, De Leenheer E, De Raeve H. Role of CCR1 and CCR5 in homing and growth of MM and in the development of osteolytic lesions: a study in the 5TMM model. Clin Exp Metastasis 2006; 23(5–6):291–300.PubMedCrossRefGoogle Scholar
  81. 81.
    Oba Y, Lee JW, Ehrlich LA, et al. MIP-1alpha utilizes both CCR1 and CCR5 to induce osteoclast formation and increase adhesion of MMC to marrow stromal cells. Exp Hematol 2005; 33(3):272–278.PubMedCrossRefGoogle Scholar
  82. 82.
    Alsayed Y, Ngo H, Runnels J, et al. Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in MM Blood 2007; 109:2708–2717.PubMedGoogle Scholar
  83. 83.
    Zannettino AC, Farrugia AN, Kortesidis A, et al. Elevated serum levels of stromal-derived factor 1-alpha are associated with increased osteoclast activity and osteo-lytic bone disease in MM patients Cancer Res 2005; 1700–1709.Google Scholar
  84. 84.
    Abe M, Hiura K, Matsumoto T, et al. Osteoclasts enhance MM cell growth and survival via cell-cell contact: a vicious cycle between bone destruction and MM expansion. Blood 2004; 104:2848–2491.CrossRefGoogle Scholar
  85. 85.
    Michigami T, Shimizu N, Williams PJ, et al. Cell-cell contact between marrow stromal cells and MMC via VCAM-1 and alpha(4)beta(1)-integrin enhances production of osteoclast-stimulating activity. Blood 2000; 96:1953–1960.PubMedGoogle Scholar
  86. 86.
    Mori Y, Shimizu N, Dallas M, et al. Anti-(alpha)4 integrin antibody suppresses the development of MM and associated osteoclasic osteolysis. Blood 2004; 104(7):2149–2154.PubMedCrossRefGoogle Scholar
  87. 87.
    Croucher PI, Shipman CM, Lippitt J, et al. Osteoprotegerin inhabits the development of osteolytic bone disease in multiple myeloma. Blood 2001; 98(13):3534–3540.PubMedCrossRefGoogle Scholar
  88. 88.
    Croucher PI, De Hendrik R, Perry MJ, et al. Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival. J Bone Miner Res 2003; 18(3):482–492.PubMedCrossRefGoogle Scholar
  89. 89.
    Dhodapkar MV, Singh J, Mehta J, et al. Anti-myeloma activity of pamidronate in vivo. Br J Haematol 1998; 103(2):530–532.PubMedCrossRefGoogle Scholar
  90. 90.
    Berenson JR, Lichtenstein A, Porter L, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group J Clin Oncol 1998; 16(2):593–602.PubMedGoogle Scholar
  91. 91.
    Yaccoby S, Wezeman MJ, Henderson A, et al. Cancer and the microenvironment: myeloma-osteoclast interactions as a model Cancer Res 2004; 64(6):2016–2023.PubMedCrossRefGoogle Scholar
  92. 92.
    Tanaka Y, Abe M, Hiasa M, et al. Myeloma cell-osteoclast interaction enhances angiogenesis together with bone resorption: a role for vascular endothelial cell growth factor and osteopontin Clin Cancer Res 2007; 13(3):816–823.PubMedCrossRefGoogle Scholar
  93. 93.
    Moreaux J, Legouffe E, Jourdan E, et al. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood 2004; 103(8):3148–3157.PubMedCrossRefGoogle Scholar
  94. 94.
    Abe M, Kido S, Hiasa M, et al. BAFF and APRIL as osteoclast-derived survival factors for myeloma cells: a rationale for TACI-Fc treatment in patients with multiple myeloma Leukemia 2006; 20(7):1313–1315.PubMedCrossRefGoogle Scholar
  95. 95.
    Moreaux J, Cremer FW, Reme T, et al. The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature Blood 2005; 106(3):1021–1030.PubMedCrossRefGoogle Scholar
  96. 96.
    Yin L. Chondroitin synthase 1 is a key molecule in MM cell-osteoclast interactions. J Biol Chem 2005; 280(16):15666–15672.PubMedCrossRefGoogle Scholar
  97. 97.
    Jundt F, Pröbsting KS, Anagnostopoulos I, et al. Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells. Blood 2004; 103(9):3511–3515.PubMedCrossRefGoogle Scholar
  98. 98.
    Nefedova Y, Cheng P, Alsina M, et al. Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines Blood 2004; 103(9):3503–3510.PubMedCrossRefGoogle Scholar
  99. 99.
    Houde C, Li Y, Song L, et al. Overexpression of the NOTCH ligand JAG2 in malignant plasma cells from MM patients and cell lines. Blood 2004; 104:3697–3704.PubMedCrossRefGoogle Scholar
  100. 100.
    Dallas SL, Rosser JL, Mundy GR, Bonewald LF. Proteolysis of latent transforming growth factor-beta (TGF-beta)-binding protein-1 by osteoclasts. A cellular mechanism for release of TGF-beta from bone matrix. J Biol Chem 2002; 277(24):21352–21360.PubMedCrossRefGoogle Scholar
  101. 101.
    Hauschka PV, Chen TL, Mavrakos AE. Polypeptide growth factors in bone matrix. Ciba Found Symp 1988; 136:207–225.PubMedGoogle Scholar
  102. 102.
    Qiang YW, Yao L, Tosato G, Rudikoff S. Insulin-like growth factor I induces migration and invasion of human MMC Blood 2004; 103:301–308.PubMedCrossRefGoogle Scholar
  103. 103.
    Ferlin M, Noraz N, Hertogh C, et al. Insulin-like growth factor induces the survival and proliferation of MMC through an interleukin-6-independent transduction pathway. Br J Haematol 2000; 111(2):626–634.PubMedCrossRefGoogle Scholar
  104. 104.
    Urashima M, Ogata A, Chauhan D, et al. Transforming growth factor-beta 1: differential effects on multiple myeloma versus normal B cells Blood 1996; 87(5):1928–1938.PubMedGoogle Scholar
  105. 105.
    Hayashi T, Hideshima T, Nguyen AN, et al. Transforming growth factor beta receptor I kinase inhibitor down-regulates cytokine secretion and MM cell growth in the BM microenvironment. Clin Cancer Res 2004; 10(22):7540–7546.PubMedCrossRefGoogle Scholar
  106. 106.
    Kehrl JH, Roberts AB, Wakefield LM, et al. Transforming growth factor beta is an important immunomodulatory protein for human B lymphocytes. J Immunol 1986; 137(12):3855–3860.PubMedGoogle Scholar
  107. 107.
    Kyrtsonis MC, Repa C, Dedoussis GV, et al. Serum transforming growth factor-beta 1 is related to the degree of immunoparesis in patients with multiple myeloma. Med Oncol 1998; 15(2):124–128.PubMedCrossRefGoogle Scholar
  108. 108.
    Amoroso SR, Huang N, Roberts AB, et al. Consistent loss of functional transforming growth factor beta receptor expression in murine plasmacytomas. Proc Natl Acad Sci USA 1998; 95(1):189–194.PubMedCrossRefGoogle Scholar
  109. 109.
    Bataille R, Chappard D, Marcelli C, et al. Recruitment of new osteoblasts and osteoclasts is the earliest critical event in the pathogenesis of human multiple myeloma. J Clin Invest 1991; 88(1):62–66.PubMedCrossRefGoogle Scholar
  110. 110.
    Evans CE, Ward C, Rathour L, et al. MM affects both the growth and function of human OBL-like cells Clin Exp Metastasis 1992; 10:33–38.PubMedCrossRefGoogle Scholar
  111. 111.
    Giuliani N, Rizzoli V, Roodman G. MM bone disease: pathophysiology of OBL inhibition. Blood 2006; 108:3992–3996.PubMedCrossRefGoogle Scholar
  112. 112.
    Tian E, Zhan F, Walker E, et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in MM N Engl J Med 2003; 349:2483–2494.PubMedCrossRefGoogle Scholar
  113. 113.
    Yaccoby S, Ling W, Zhan F, et al. Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and MM growth in vivo. Blood 2007; 109:2106–2111.PubMedCrossRefGoogle Scholar
  114. 114.
    Oshima T, Abe M, Matsumoto T. MMC suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2 Blood 2005; 106:3160–3165.PubMedCrossRefGoogle Scholar
  115. 115.
    Glass D, Bialek P, Karsenty G, et al. Canonical Wnt signaling in differentiated OBL controls osteoblast differentiation. Dev Cell 2005; 8:751–764.PubMedCrossRefGoogle Scholar
  116. 116.
    Yaccoby S, Wezeman MJ, Zangari M, et al. Inhibitory effects of osteoblasts and increased bone formation on myeloma in novel culture systems and a myeloma-tous mouse model Haematologica 2006; 91(2):192–199.PubMedGoogle Scholar
  117. 117.
    Qiang Y, Walsh K, Rudikoff S. Wnts induce migration and invasion of MM plasma cells Blood 2005; 106:1786–1793.PubMedCrossRefGoogle Scholar
  118. 118.
    Nelson W, Russe R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science 2004; 303:1483–1487.PubMedCrossRefGoogle Scholar
  119. 119.
    Derkson PWB, Tjin E, Pals T. Illegitimate Wnt signaling promotes proliferation of MMC. Proc Natl Acad Sci 2004; 101:6122–6127.CrossRefGoogle Scholar
  120. 120.
    Miller JR, Hking AM, Brown JD, Moon RT. Mechanism and function of signal transduction by the Wnt/beta-catenin and Wnt/Ca2+ pathways. Oncogene 1999; 18(55):7860–7872.PubMedCrossRefGoogle Scholar
  121. 121.
    Staal FJ, Clevers HC. WNT signaling and haematopoiesis: a WNT-WNT situation. Nat Rev Immunol 2005; 5(1):21–30.PubMedCrossRefGoogle Scholar
  122. 122.
    Dosen G, Tenstad E, Nygren MK, et al. Wnt expression and canonical Wnt signaling in human BM B lymphopoiesis BMC Immunol 2006; 29:7–13.Google Scholar
  123. 123.
    Herbst A, Kolligs FT. Wnt signaling as a therapeutic target for cancer. Methods Mol Biol 2007; 361:63–91.PubMedGoogle Scholar
  124. 124.
    Karim R, Tse G, Putti T, et al. The significance of the Wnt pathway in the pathology of human cancers Pathology 2004; 36(2):120–128.PubMedCrossRefGoogle Scholar
  125. 125.
    Giuliani N, Colla S, Marandi F, et al. MMC blk RUNX2/CBFA1 activity in human BM OBL progenitors and inhibit OBL formation and differentiation. Blood 2005; 106:2472–2483.PubMedCrossRefGoogle Scholar
  126. 126.
    Weitzmann MN, Roggia C, Tpraodp G, et al. Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency. J Clin Invest 2002; 110:1643–1650.PubMedGoogle Scholar
  127. 127.
    Gaur T, Lengner CJ, Hovhannisyan H, et al. Canonical Wnt signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J Biol Chem 2005; 280:33132–33140.PubMedCrossRefGoogle Scholar
  128. 128.
    Kahler RA, Westendorf JJ. Lymphoid enhancer factor-1 and beta-catenin inhibit Runx2-dependent transcriptional activation of the osteocalcin promoter. J Biol Chem 2003; 278(14):11937–11944.PubMedCrossRefGoogle Scholar
  129. 129.
    Reinhold MI, Naski MC. Direct interactions of Runx2 and canonical Wnt signaling induce FGF18 J Biol Chem 2007; 282(6):3653–3663.PubMedCrossRefGoogle Scholar
  130. 130.
    Haque T, Nakada S, Hamdy RC. A review of FGF18: Its expression, signaling pathways and possible functions during embryogenesis and post-natal development. Histol Histopathol 2007; 22(1):97–105.PubMedGoogle Scholar
  131. 131.
    ThirunavukkarasuK,Halliday DL, Miles RR, et al. The OBL-specific transcription factor Cbfa1 contributes to the expression of osteoprotegerin, a potent inhibitor of osteoclast differentiation and function J Biol Chem 2000; 2675:25163–25172.CrossRefGoogle Scholar
  132. 132.
    Ely SA, Knowles DM. Expression of CD56/neural cell adhesion molecule correlates with the presence of lytic bone lesions in multiple myeloma and distinguishes myeloma from monoclonal gammopathy of undetermined significance and lymphomas with plasmacytoid differentiation. Am J Pathol 2002; 160(4):1293–1299.PubMedCrossRefGoogle Scholar
  133. 133.
    Ehrlich LA, Chung HY, Ghobrial I, et al. IL-3 is a potential inhibitor of OBL differentiation in MM Blood 2005; 106:1407–1414.PubMedCrossRefGoogle Scholar
  134. 134.
    Giuliani N, Morandi F, Tagliaferri S, et al. Interleukin-3 (IL-3) is overexpressed by T lymphocytes in MM patients Blood 2006; 107:841–842.PubMedCrossRefGoogle Scholar
  135. 135.
    Lee JW, Chung HY, Ehrilch LA, et al. IL-3 expression by MMC increases both osteoclast formation and growth of MMC Blood 2004; 103:2308–2315.PubMedCrossRefGoogle Scholar
  136. 136.
    Silvestris F, Cafforio P, Tucci M, et al. Upregulation of OBL apoptosis by malignant plasma cells: a role in MM bone disease Br J Haematol 2003; 122:39–52.PubMedCrossRefGoogle Scholar
  137. 137.
    Tinhofer I, Biedermann R, Krismer M, et al. A role of TRAIL in killing OBL by MMC. FASEB J 2006; 20:759–761.PubMedGoogle Scholar
  138. 138.
    Shipman CM, Croucher PI. Osteoprotegerin is a soluble decoy receptor for tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand and can function as a paracrine survival factor for human myeloma cells Cancer Res 2003; 63(5):912–916.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Tomer M. Mark
    • 1
  • Roger N. Pearse
    • 1
  1. 1.Weil Medical College of Cornell UniveristyNew YorkUSA

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