• 1
    Kyle RA. Multiple myeloma: review of 869 cases. Mayo Clin Proc. 1975; 50: 2940.
  • 2
    Durie BG, Salmon SE. Cellular kinetics staging, and immunoglobulin synthesis in multiple myeloma. Annu Rev Med. 1975; 26: 283288.
  • 3
    Resnick D, Greenway GD, Bardwick PA, Zvaifler NJ, Gill GN, Newman DR. Plasma-cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes: the POEMS syndrome. Distinctive radiographic abnormalities. Radiology. 1981; 140: 1722.
  • 4
    Bardwick PA, Zvaifler NJ, Gill GN, Newman D, Greenway GD, Resnick DL. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes: the POEMS syndrome. Report on two cases and a review of the literature. Medicine (Baltimore). 1980; 59: 311322.
  • 5
    Bataille R, Manolagas SC, Berenson JR. Pathogenesis and management of bone lesions in multiple myeloma. Hematol Oncol Clin North Am. 1997; 11: 349361.
  • 6
    Durie BG, Salmon SE, Mundy GR. Relation of osteoclast activating factor production to extent of bone disease in multiple myeloma. Br J Haematol. 1981; 47: 2130.
  • 7
    Mundy GR, Raisz LG, Cooper RA, Schechter GP, Salmon SE. Evidence for the secretion of an osteoclast stimulating factor in myeloma. N Engl J Med. 1974; 291: 10411046.
  • 8
    Roodman GD. Biology of osteoclast activation in cancer. J Clin Oncol. 2001; 19: 35623571.
  • 9
    Pearse RN, Sordillo EM, Yaccoby S, et al. Multiple myeloma disrupts the TRANCE/osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression. Proc Natl Acad Sci USA. 2001; 98: 1158111586.
  • 10
    Sezer O, Heider U, Jakob C, Eucker J, Possinger K. Human bone marrow myeloma cells express RANKL. J Clin Oncol. 2002; 20: 353354.
  • 11
    Giuliani N, Bataille R, Mancini C, Lazzaretti M, Barille S. Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment. Blood. 2001; 98: 35273533.
  • 12
    Roux S, Meignin V, Quillard J, et al. RANK (receptor activator of nuclear factor-kappa B) and RANKL expression in multiple myeloma. Br J Haematol. 2002; 117: 8692.
  • 13
    Seidel C, Hjertner O, Abildgaard N, et al. Serum osteoprotegerin levels are reduced in patients with multiple myeloma with lytic bone disease. Blood. 2001; 98: 22692271.
  • 14
    Yasuda H, Shima N, Nakagawa N, et al. Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology. 1998; 139: 13291337.
  • 15
    Takai H, Kanematsu M, Yano K, et al. Transforming growth factor-beta stimulates the production of osteoprotegerin/osteoclastogenesis inhibitory factor by bone marrow stromal cells. J Biol Chem. 1998; 273: 2709127096.
  • 16
    Anderson DM, Maraskovsky E, Billingsley WL, et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 1997; 390: 175179.
  • 17
    Wong BR, Rho J, Arron J, et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J Biol Chem. 1997; 272: 25190194.
  • 18
    Yasuda H, Shima N, Nakagawa N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA. 1998; 95: 35973602.
  • 19
    Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998; 93: 165176.
  • 20
    Kong YY, Yoshida H, Sarosi I, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999; 397: 315323.
  • 21
    Kong YY, Feige U, Sarosi I, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature. 1999; 402: 304309.
  • 22
    Kim N, Odgren PR, Kim DK, Marks SC Jr., Choi Y. Diverse roles of the tumor 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 USA. 2000; 97: 1090510910.
  • 23
    Fata JE, Kong YY, Li J, et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell. 2000; 103: 4150.
  • 24
    Kim D, Mebius RE, MacMicking JD, et al. Regulation of peripheral lymph node genesis by the tumor necrosis factor family member TRANCE. J Exp Med. 2000; 192: 14671478.
  • 25
    Green EA, Choi Y, Flavell RA. Pancreatic lymph node-derived CD4(+)CD25(+) Treg cells: highly potent regulators of diabetes that require TRANCE-RANK signals. Immunity. 2002; 16: 183191.
  • 26
    Nagai M, Kyakumoto S, Sato N. Cancer cells responsible for humoral hypercalcemia express mRNA encoding a secreted form of ODF/TRANCE that induces osteoclast formation. Biochem Biophys Res Commun. 2000; 269: 532536.
  • 27
    Lum L, Wong BR, Josien R, et al. Evidence for a role of a tumor 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. 1999; 274: 1361313618.
  • 28
    Schlondorff J, Lum L, Blobel CP. Biochemical and pharmacological criteria define two shedding activities for TRANCE/OPGL that are distinct from the tumor necrosis factor alpha convertase. J Biol Chem. 2001; 276: 1466514674.
  • 29
    Lam J, Nelson CA, Ross FP, Teitelbaum SL, Fremont DH. Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity. J Clin Invest. 2001; 108: 971979.
  • 30
    Ito S, Wakabayashi K, Ubukata O, Hayashi S, Okada F, Hata T. Crystal structure of the extracellular domain of mouse RANK ligand at 2.2-A resolution. J Biol Chem. 2002; 277: 66316636.
  • 31
    Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997; 89: 309319.
  • 32
    Kwon BS, Wang S, Udagawa N, et al. TR1, a new member of the tumor necrosis factor receptor superfamily, induces fibroblast proliferation and inhibits osteoclastogenesis and bone resorption. FASEB J. 1998; 12: 845854.
  • 33
    Tan KB, Harrop J, Reddy M, et al. Characterization of a novel TNF-like ligand and recently described TNF ligand and TNF receptor superfamily genes and their constitutive and inducible expression in hematopoietic and non-hematopoietic cells. Gene. 1997; 204: 3546.
  • 34
    Yun TJ, Chaudhary PM, Shu GL, et al. OPG/FDCR-1, a TNF receptor family member, is expressed in lymphoid cells and is up-regulated by ligating CD40. J Immunol. 1998; 161: 61136121.
  • 35
    Hsu H, Lacey DL, Dunstan CR, et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA. 1999; 96: 35403545.
  • 36
    Dhore CR, Cleutjens JP, Lutgens E, et al. Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 2001; 21: 19982003.
  • 37
    Min H, Morony S, Sarosi I, et al. Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis. J Exp Med. 2000; 192: 463474.
  • 38
    Kanematsu M, Sato T, Takai H, Watanabe K, Ikeda K, Yamada Y. Prostaglandin E2 induces expression of receptor activator of nuclear factor-kappa B ligand/osteoprotegrin ligand on pre-B cells: implications for accelerated osteoclastogenesis in estrogen deficiency. J Bone Miner Res. 2000; 15: 13211329.
  • 39
    Horwood NJ, Elliott J, Martin TJ, Gillespie MT. Osteotropic agents regulate the expression of osteoclast differentiation factor and osteoprotegerin in osteoblastic stromal cells. Endocrinology. 1998; 139: 47434746.
  • 40
    Kotake S, Udagawa N, Takahashi N, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999; 103: 13451352.
  • 41
    Hofbauer LC, Lacey DL, Dunstan CR, Spelsberg TC, Riggs BL, Khosla S. Interleukin-1 beta and tumor necrosis factor-alpha, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone. 1999; 25: 255259.
  • 42
    Nakagawa N, Kinosaki M, Yamaguchi K, et al. RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem Biophys Res Commun. 1998; 253: 395400.
  • 43
    Dougall WC, Glaccum M, Charrier K, et al. RANK is essential for osteoclast and lymph node development. Genes Dev. 1999; 13: 24122424.
  • 44
    Li J, Sarosi I, Yan XQ, et al. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA. 2000; 97: 15661571.
  • 45
    Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001; 104: 487501.
  • 46
    Chung JY, Park YC, Ye H, Wu H. All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. J Cell Sci. 2002; 115: 679688.
  • 47
    Darnay BG, Haridas V, Ni J, Moore PA, Aggarwal BB. Characterization of the intracellular domain of receptor activator of NF-kappa B (RANK). Interaction with tumor necrosis factor receptor-associated factors and activation of NF-kappa b and c-Jun N-terminal kinase. J Biol Chem. 1998; 273: 2055120555.
  • 48
    Wong BR, Josien R, Lee SY, Vologodskaia M, Steinman RM, Choi Y. The TRAF family of signal transducers mediates NF-kappa B activation by the TRANCE receptor. J Biol Chem. 1998; 273: 2835528359.
  • 49
    Kim HH, Lee DE, Shin JN, et al. Receptor activator of NF-kappa B recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase. FEBS Lett. 1999; 443: 297302.
  • 50
    Nishitoh H, Saitoh M, Mochida Y, et al. ASK1 is essential for JNK/SAPK activation by TRAF2. Mol Cell. 1998; 2: 389395.
  • 51
    Hoeflich KP, Yeh WC, Yao Z, Mak TW, Woodgett JR. Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1 (ASK1). Oncogene. 1999; 18: 58145820.
  • 52
    Wong BR, Besser D, Kim N, et al. TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol Cell. 1999; 4: 10411049.
  • 53
    Xing L, Venegas AM, Chen A, et al. Genetic evidence for a role for Src family kinases in TNF family receptor signaling and cell survival. Genes Dev. 2001; 15: 241253.
  • 54
    Arron JR, Vologodskaia M, Wong BR, et al. A positive regulatory role for Cbl family proteins in tumor necrosis factor-related activation-induced cytokine (trance) and CD40L-mediated Akt activation. J Biol Chem. 2001; 276: 3001130017.
  • 55
    Mizukami J, Takaesu G, Akatsuka H, et al. Receptor activator of NF-kappa B ligand (RANKL) activates TAK1 mitogen-activated protein kinase kinase kinase through a signaling complex containing RANK, TAB2, and TRAF6. Mol Cell Biol. 2002; 22: 9921000.
  • 56
    Lomaga MA, Yeh WC, Sarosi I, et al. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 1999; 13: 10151024.
  • 57
    Boyce BF, Yoneda T, Lowe C, Soriano P, Mundy GR. Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice. J Clin Invest. 1992; 90: 16221627.
  • 58
    Takayanagi H, Ogasawara K, Hida S, et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature. 2000; 408: 600605.
  • 59
    Takayanagi H, Kim S, Matsuo K, et al. RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta. Nature. 2002; 416: 744749.
  • 60
    Bucay N, Sarosi I, Dunstan CR, et al. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998; 12: 12601268.
  • 61
    Hofbauer LC, Dunstan CR, Spelsberg TC, Riggs BL, Khosla S. Osteoprotegerin production by human osteoblast lineage cells is stimulated by vitamin D, bone morphogenetic protein-2, and cytokines. Biochem BiophysRes Commun. 1998; 250: 776781.
  • 62
    Morinaga T, Nakagawa N, Yasuda H, Tsuda E, Higashio K. Cloning and characterization of the gene encoding human osteoprotegerin/osteoclastogenesis-inhibitory factor. Eur J Biochem. 1998; 254: 685691.
  • 63
    Emery JG, McDonnell P, Burke MB, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem. 1998; 273: 1436314367.
  • 64
    Holen I, Croucher PI, Hamdy FC, Eaton CL. Osteoprotegerin (OPG) is a survival factor for human prostate cancer cells. Cancer Res. 2002; 62: 16191623.
  • 65
    Malyankar UM, Scatena M, Suchland KL, Yun TJ, Clark EA, Giachelli CM. Osteoprotegerin is an alpha vbeta 3-induced, NF-kappa B-dependent survival factor for endothelial cells. J Biol Chem. 2000; 275: 2095920962.
  • 66
    Willard D, Chen WJ, Barrett G, et al. Expression, purification, and characterization of the human receptor activator of NF-kappa B ligand (RANKL) extracellular domain. Protein Exp Purif. 2000; 20: 4857.
  • 67
    Oyajobi BO, Anderson DM, Traianedes K, Williams PJ, Yoneda T, Mundy GR. Therapeutic efficacy of a soluble receptor activator of nuclear factor kappa B-IgG Fc fusion protein in suppressing bone resorption and hypercalcemia in a model of humoral hypercalcemia of malignancy. Cancer Res. 2001; 61: 25722578.
  • 68
    Croucher PI, Shipman CM, Lippitt J, et al. Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma. Blood. 2001; 98: 35343540.
  • 69
    Pearse RN, Wong BR, Sordillo EM, et al. The role of the osteoclast differentiation factor TRANCE in myeloma-associated bone destruction. Stockholm, VIIth International Myeloma Workshop, 1999.
  • 70
    Borset M, Hjertner O, Yaccoby S, Epstein J, Sanderson RD. Syndecan-1 is targeted to the uropods of polarized myeloma cells where it promotes adhesion and sequesters heparin-binding proteins. Blood. 2000; 96: 25282536.
  • 71
    Bachmann MF, Wong BR, Josien R, Steinman RM, Oxenius A, Choi Y. TRANCE, a tumor necrosis factor family member critical for CD40 ligand-independent T helper cell activation. J Exp Med. 1999; 189: 10251031.
  • 72
    Mariani SM, Matiba B, Armandola EA, Krammer PH. Interleukin 1 beta-converting enzyme related proteases/caspases are involved in TRAIL-induced apoptosis of myeloma and leukemia cells. J Cell Biol. 1997; 137: 221229.
  • 73
    Mitsiades CS, Treon SP, Mitsiades N, et al. TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications. Blood. 2001; 98: 795804.
  • 74
    Alsina M, Boyce B, Devlin RD, et al. Development of an in vivo model of human multiple myeloma bone disease. Blood. 1996; 87: 14951501.
  • 75
    Urashima M, Chen BP, Chen S, et al. The development of a model for the homing of multiple myeloma cells to human bone marrow. Blood. 1997; 90: 754765.
  • 76
    Yaccoby S, Barlogie B, Epstein J. Primary myeloma cells growing in SCID-hu mice: a model for studying the biology and treatment of myeloma and its manifestations. Blood. 1998; 92: 29082913.
  • 77
    Yaccoby S, Pearse RN, Johnson CL, Barlogie B, Choi Y, Epstein J. Myeloma interacts with the bone marrow microenvironment to induce osteoclastogenesis and is dependent on osteoclast activity. Br J Haematol. 2002; 116: 278290.
  • 78
    Nosaka K, Miyamoto T, Sakai T, Mitsuya H, Suda T, Matsuoka M. Mechanism of hypercalcemia in adult T-cell leukemia: overexpression of receptor activator of nuclear factor kappa B ligand on adult T-cell leukemia cells. Blood. 2002; 99: 634640.
  • 79
    Wong BR, Josien R, Lee SY, et al. TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J Exp Med. 1997; 186: 20752080.
  • 80
    Sze DM, Toellner KM, Garcia d, V, Taylor DR, MacLennan IC. Intrinsic constraint on plasmablast growth and extrinsic limits of plasma cell survival. J Exp Med. 2000; 192: 813821.
  • 81
    Kim YM, Kim YM, Lee YM, et al. TNF-related activation-induced cytokine (TRANCE) induces angiogenesis through the activation of Src and phospholipase C (PLC) in human endothelial cells. J Biol Chem. 2002; 277: 67996805.
  • 82
    Kincade PW. B lymphopoiesis: global factors, local control. Proc Natl Acad Sci USA. 1994; 91: 28889.
  • 83
    Tagaya H, Kunisada T, Yamazaki H, et al. Intramedullary and extramedullary B lymphopoiesis in osteopetrotic mice. Blood. 2000; 95: 33633370.
  • 84
    Yun TJ, Tallquist MD, Aicher A, et al. Osteoprotegerin, a crucial regulator of bone metabolism, also regulates B cell development and function. J Immunol. 2001; 166: 14821491.
  • 85
    Treon SP, Teoh G, Urashima M, et al. Anti-estrogens induce apoptosis of multiple myeloma cells. Blood. 1998; 92: 17491757.
  • 86
    De Vos J, Couderc G, Tarte K, et al. Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays. Blood. 2001; 98: 771780.
  • 87
    Shipman CM, Rogers MJ, Vanderkerken K, et al. Bisphosphonates—mechanisms of action in multiple myeloma. Acta Oncol. 2000; 39: 829835.
  • 88
    Apperley JF, Croucher PI. Bisphosphonates in multiple myeloma. Pathol Biol (Paris). 1999; 47: 178181.
  • 89
    Musto P. The role of bisphosphonates for the treatment of bone disease in multiple myeloma. Leuk Lymphoma. 1998; 31: 453462.
  • 90
    Plotkin LI, Weinstein RS, Parfitt AM, Roberson PK, Manolagas SC, Bellido T. Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest. 1999; 104: 13631374.
  • 91
    Russell RG, Rogers MJ. Bisphosphonates: from the laboratory to the clinic and back again. Bone. 1999; 25: 97106.
  • 92
    Vitte C, Fleisch H, Guenther HL. Bisphosphonates induce osteoblasts to secrete an inhibitor of osteoclast-mediated resorption. Endocrinology. 1996; 137: 23242333.
  • 93
    Viereck V, Emons G, Lauck V, et al. Bisphosphonates pamidronate and zoledronic acid stimulate osteoprotegerin production by primary human osteoblasts. Biochem Biophys Res Commun. 2002; 291: 680686.
  • 94
    Klein B, Bataille R. Cytokine network in human multiple myeloma. Hematol Oncol Clin North Am. 1992; 6: 273284.
  • 95
    Murakami T, Yamamoto M, Ono K, et al. Transforming growth factor-beta 1 increases mRNA levels of osteoclastogenesis inhibitory factor in osteoblastic/stromal cells and inhibits the survival of murine osteoclast-like cells. Biochem Biophys Res Commun. 1998; 252: 747752.
  • 96
    Brandstrom H, Jonsson KB, Ohlsson C, Vidal O, Ljunghall S, Ljunggren O. Regulation of osteoprotegerin mRNA levels by prostaglandin E2 in human bone marrow stroma cells. Biochem Biophys Res Commun. 1998; 247: 338341.
  • 97
    Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Spelsberg TC, Riggs BL. Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology. 1999; 140: 43674370.
  • 98
    Vidal NO, Brandstrom H, Jonsson KB, Ohlsson C. Osteoprotegerin mRNA is expressed in primary human osteoblast-like cells: down-regulation by glucocorticoids. J Endocrinol. 1998; 159: 191195.
  • 99
    Hofbauer LC, Gori F, Riggs BL, et al. Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology. 1999; 140: 43824389.
  • 100
    Brandstrom H, Jonsson KB, Vidal O, Ljunghall S, Ohlsson C, Ljunggren O. Tumor necrosis factor-alpha and -beta upregulate the levels of osteoprotegerin mRNA in human osteosarcoma MG-63 cells. Biochem Biophys Res Commun. 1998; 248: 454457.
  • 101
    Mukohyama H, Ransjo M, Taniguchi H, Ohyama T, Lerner UH. The inhibitory effects of vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide on osteoclast formation are associated with upregulation of osteoprotegerin and downregulation of RANKL and RANK. Biochem Biophys Res Commun. 2000; 271: 158163.
  • 102
    Vidal ON, Sjogren K, Eriksson BI, Ljunggren O, Ohlsson C. Osteoprotegerin mRNA is increased by interleukin-1 alpha in the human osteosarcoma cell line MG-63 and in human osteoblast-like cells. Biochem Biophys Res Commun. 1998; 248: 696700.