Human T-cell leukemia virus type-1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL). Hypercalcemia is common in patients with ATL. These patients rarely develop metastatic calcification and acute pancreatitis. The underlying pathogenesis of this condition is osteoclast hyperactivity with associated overproduction of parathyroid hormone-related protein, which results in hypercalcemia in association with bone demineralization. The discovery of the osteoclast differentiation factor receptor activator of nuclear factor-κB ligand (RANKL), its receptor RANK, and its decoy receptor osteoprotegerin (OPG), enhanced our understanding of the mechanisms of ATL-associated hypercalcemia. Macrophage inflammatory protein-1-α, tumor necrosis factor-α, interleukin-1, and interleukin-6 are important molecules that enhance the migration and differentiation of osteoclasts and the associated enhanced production of RANKL for osteoblast formation. In this paper, we focus on metastatic calcification and acute pancreatitis in ATL, highlighting recent advances in the understanding of the molecular role of the RANKL/RANK/OPG system including its interaction with various cytokines and calciotropic hormones in the regulation of osteoclastogenesis for bone resorption in hypercalcemic ATL patients. 1. Introduction Adult T-cell leukemia (ATL) was first reported as a new clinical entity in 1977 in Japan [1, 2]. The predominant physical findings are skin involvement, such as erythroderma and nodule formation due to the infiltration of neoplastic cells, lymphadenopathy, and hepatosplenomegaly. The ATL cells are of mature T-helper phenotype and have a characteristic appearance with especially indented or lobulated nuclei. Hypercalcemia is common in patients with ATL, and such patients often show increased numbers of osteoclasts. A type C retrovirus was isolated from patients with cutaneous T-cell lymphoma by Poiesz and colleagues in 1980 [3]. This virus was later renamed human T-cell leukemia virus type 1 (HTLV-1). In 1981, Hinuma et al. [4] and Yoshida and colleagues [5] reported the isolation of a type C retrovirus named adult T-cell leukemia virus. The two isolates of human leukemia virus, HTLV-1, and adult T-cell leukemia virus, were later confirmed to be the same species of human retrovirus HTLV type I (US isolate) and ATLV (Japanese isolate) [6]. Approximately 16 to 20 million people are infected with HTLV-1 worldwide, and 1 to 5% of the infected individuals develop ATL during their lifetime [7] caused by the transformation of their CD4+ T cells [8]. In Japan, it is
References
[1]
K. Takatsuki, T. Uchiyama, K. Sagawa, and J. Yodoi, “Adult T cell leukemia in Japan,” in Topics in Hematology, S. Seno, F. Takatu, and S. Irino, Eds., pp. 73–77, Excerpta Medica, Amsterdam, The Netherlands, 1977.
[2]
T. Uchiyama, J. Yodoi, K. Sagawa, K. Takatsuki, and H. Uchino, “Adult T-cell leukemia: clinical and hematologic features of 16 cases,” Blood, vol. 50, no. 3, pp. 481–492, 1977.
[3]
B. J. Poiesz, F. W. Ruscetti, A. F. Gazdar, P. A. Bunn, J. D. Minna, and R. C. Gallo, “Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma,” Proceedings of the National Academy of Sciences of the United States of America, vol. 77, no. 12, pp. 7415–7419, 1980.
[4]
Y. Hinuma, K. Nagata, and M. Hanaoka, “Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera,” Proceedings of the National Academy of Sciences of the United States of America, vol. 78, no. 10, pp. 6476–6480, 1981.
[5]
M. Yoshida, I. Miyoshi, and Y. Hinuma, “Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 79, no. 6, pp. 2031–2035, 1982.
[6]
T. Watanabe, M. Seiki, and M. Yoshida, “HTLV type I (U.S. isolate) and ATLV (Japanese isolate) are the same species of human retrovirus,” Virology, vol. 133, no. 1, pp. 238–241, 1984.
[7]
T. Ishikawa, “Current status of therapeutic approaches to adult T-Cell leukemia,” International Journal of Hematology, vol. 78, no. 4, pp. 304–311, 2003.
[8]
M. Kannagi, T. Ohashi, N. Harashima, S. Hanabuchi, and A. Hasegawa, “Immunological risks of adult T-cell leukemia at primary HTLV-I infection,” Trends in Microbiology, vol. 12, no. 7, pp. 346–352, 2004.
[9]
M. Matsuoka and K. T. Jeang, “Human T-cell leukemia virus type I at age 25: a progress report,” Cancer Research, vol. 65, no. 11, pp. 4467–4470, 2005.
[10]
F. A. Proietti, A. B. F. Carneiro-Proietti, B. C. Catalan-Soares, and E. L. Murphy, “Global epidemiology of HTLV-I infection and associated diseases,” Oncogene, vol. 24, no. 39, pp. 6058–6068, 2005.
[11]
K. Verdonck, E. González, S. van Dooren, A. M. Vandamme, G. Vanham, and E. Gotuzzo, “Human T-lymphotropic virus 1: recent knowledge about an ancient infection,” The Lancet Infectious Diseases, vol. 7, no. 4, pp. 266–281, 2007.
[12]
D. U. Gon？alves, F. A. Proietti, J. G. R. Ribas et al., “Epidemiology, treatment, and prevention of human T-cell leukemia virus type 1-associated diseases,” Clinical Microbiology Reviews, vol. 23, no. 3, pp. 577–589, 2010.
[13]
A. Gessain, F. Barin, and J. C. Vernant, “Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis,” The Lancet, vol. 2, no. 8452, pp. 407–410, 1985.
[14]
M. Osame, K. Usuku, and S. Izumo, “HTLV-I associated myelopathy, a new clinical entity,” The Lancet, vol. 1, no. 8488, pp. 1031–1032, 1986.
[15]
M. M. Aye, E. Matsuoka, T. Moritoyo et al., “Histopathological analysis of four autopsy cases of HTLV-I-associated myelopathy/tropical spastic paraparesis: inflammatory changes occur simultaneously in the entire central nervous system,” Acta Neuropathologica, vol. 100, no. 3, pp. 245–252, 2000.
[16]
J. A. Sakai, M. Nagai, M. B. Brennan, C. A. Mora, and S. Jacobson, “In vitro spontaneous lymphoproliferation in patients with human T-cell lymphotropic virus type I-associated neurologic disease: predominant expansion of CD8+ T cells,” Blood, vol. 98, no. 5, pp. 1506–1511, 2001.
[17]
R. Kubota, S. S. Soldan, R. Martin, and S. Jacobson, “Selected cytotoxic T lymphocytes with high specificity for HTLV-1 in cerebrospinal fluid from a HAM/TSP patient,” Journal of NeuroVirology, vol. 8, no. 1, pp. 53–57, 2002.
[18]
P. K. C. Goon, T. Igakura, E. Hanon et al., “High circulating frequencies of tumor necrosis factor alpha- and interleukin-2-secreting human T-lymphotropic virus type 1 (HTLV-1)-specific CD4+ T cells in patients with HTLV-1-associated neurological disease,” Journal of Virology, vol. 77, no. 17, pp. 9716–9722, 2003.
[19]
P. A. Muraro, K. P. Wandinger, B. Bielekova et al., “Molecular tracking of antigen-specific T cell clones in neurological immune-mediated disorders,” Brain, vol. 126, part 1, pp. 20–31, 2003.
[20]
S. Olindo, A. Lézin, P. Cabre et al., “HTLV-1 proviral load in peripheral blood mononuclear cells quantified in 100 HAM/TSP patients: a marker of disease progression,” Journal of the Neurological Sciences, vol. 237, no. 1-2, pp. 53–59, 2005.
[21]
M. Senba, K. Kawai, S. Chiyoda, and O. Takahara, “Metastatic liver calcification in adult T-cell leukemia-lymphoma associated with hypercalcemia,” American Journal of Gastroenterology, vol. 85, no. 9, pp. 1202–1203, 1990.
[22]
M. Senba and K. Kawai, “Metastatic calcification due to hypercalcemia in adult T-cell leukemia-lymphoma (ATLL),” Zentralblatt für Pathologie, vol. 137, no. 4, pp. 341–345, 1991.
[23]
M. Senba, T. Nakamura, K. Kawai, and M. I. Senba, “HTLV-I and acute pancreatitis,” The Lancet, vol. 337, no. 8755, p. 1489, 1991.
[24]
M. Senba and M. I. Senba, “Acute pancreatitis associated with hyplercalcaemia in adult T-cell leukaemia-lymphoma,” Journal of Gastroenterology and Hepatology, vol. 11, no. 2, pp. 180–182, 1996.
[25]
M. Senba and K. Kawai, “Hypercalcemia and production of parathyroid hormone-like protein in adult T-cell leukemia-lymphoma,” European Journal of Haematology, vol. 48, no. 5, pp. 278–279, 1992.
[26]
S. C. Manolagas, “Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis,” Endocrine Reviews, vol. 21, no. 2, pp. 115–137, 2000.
[27]
M. Koide, S. Kinugawa, N. Takahashi, and N. Udagawa, “Osteoclastic bone resorption induced by innate immune responses,” Periodontology 2000, vol. 54, no. 1, pp. 235–246, 2010.
[28]
H. Takayanagi, “New immune connections in osteoclast formation,” Annals of the New York Academy of Sciences, vol. 1192, pp. 117–123, 2010.
[29]
K. Nosaka, T. Miyamoto, T. Sakai, H. Mitsuya, T. Suda, and M. Matsuoka, “Mechanism of hypercalcemia in adult T-cell leukemia: overexpression of receptor activator of nuclear factor κb ligand on adult T-cell leukemia cells,” Blood, vol. 99, no. 2, pp. 634–640, 2002.
[30]
G. D. Roodman, “Regulation of osteoclast differentiation,” Annals of the New York Academy of Sciences, vol. 1068, no. 1, pp. 100–109, 2006.
[31]
D. Vega, N. M. Maalouf, and K. Sakhaee, “Clinical review: the role of receptor activator of nuclear factor-κB (RANK)/RANK ligand/osteoprotegerin: clinical implications,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 12, pp. 4514–4521, 2007.
[32]
C. Parrula, B. Zimmerman, P. Nadella et al., “Expression of tumor invasion factors determines systemic engraftment and induction of humoral hypercalcemia in a mouse model of adult T-cell leukemia,” Veterinary Pathology, vol. 46, no. 5, pp. 1003–1014, 2009.
[33]
S. Fili, M. Karalaki, and B. Schaller, “Therapeutic implications of osteoprotegerin,” Cancer Cell International, vol. 9, p. 26, 2009.
[34]
A. P. Trouvin and V. Go？b, “Receptor activator of nuclear factor- B ligand and osteoprotegerin: maintaining the balance to prevent bone loss,” Clinical Interventions in Aging, vol. 5, pp. 345–354, 2010.
[35]
E. D. Chan, D. V. Morales, C. H. Welsh, M. T. McDermott, and M. I. Schwarz, “Calcium deposition with or without bone formation in the lung,” American Journal of Respiratory and Critical Care Medicine, vol. 165, no. 12, pp. 1654–1669, 2002.
[36]
R. M. Mulligan, “Metastatic calcification,” Archives of Pathology, vol. 43, no. 2, pp. 177–230, 1947.
[37]
G. D. Roodman, “Mechanisms of bone lesions in multiple myeloma and lymphoma,” Cancer, vol. 80, no. 8, pp. 1557–1563, 1997.
[38]
T. Kiyokawa, K. Yamaguchi, and M. Takeya, “Hypercalcemia and osteoclast proliferation in adult T-cell leukemia,” Cancer, vol. 59, no. 6, pp. 1187–1191, 1987.
[39]
M. Nakamura, A. Ohishi, R. Watanabe et al., “Adult T-cell leukemia with hypercalcemia-induced metastatic calcification in the lungs due to production of parathyroid hormone-related protein,” Internal Medicine, vol. 40, no. 5, pp. 409–413, 2001.
[40]
Y. Taguchi, G. Fuyuno, S. Shioya et al., “MR appearance of pulmonary metastatic calcification,” Journal of Computer Assisted Tomography, vol. 20, no. 1, pp. 38–41, 1996.
[41]
H. Kumamoto, R. Ichinohasama, T. Sawai et al., “Multiple organ failure associated with extensive metastatic calcification in a patient with an intermediate state of human T lymphotropic virus type I (HTLV-1) infection: report of an autopsy case,” Pathology International, vol. 48, no. 4, pp. 313–318, 1998.
[42]
J. Haratake, N. Ishii, A. Horie, M. Matsumoto, S. Oda, and K. Satoh, “Adult T-cell leukemia complicated by hypercalcemia: report of three autopsy cases with special reference to the etiologic factor of hypercalcemia,” Acta Pathologica Japonica, vol. 35, no. 2, pp. 437–448, 1985.
[43]
T. Hosokawa, T. Itoga, Y. Saburi, R. Mizutani, T. Fujioka, and H. Yamashita, “An autopsy case of adult T cell leukemia died of acute hemorrhagic pancreatitis,” Journal of Kyushu Hematological Society, vol. 32, no. 3-4, pp. 75–81, 1984, (in Japanese with English abstract).
[44]
Y. Dazai, I. Katoh, Y. Hara, R. Yoshida, and K. Kurihara, “Two cases of adult T-cell leukemia associated with acute pancreatitis due to hypercalcemia,” American Journal of Medicine, vol. 90, no. 2, pp. 251–254, 1991.
[45]
Y. Ono, T. Kimura, I. Nakano et al., “Acute pancreatitis induced by hypercalcaemia associated with adult T-cell leukaemia: a case report,” Journal of Gastroenterology and Hepatology, vol. 11, no. 2, pp. 193–195, 1996.
[46]
K. Kinoshita, S. Kamihira, and S. Ikeda, “Clinical, hematologic, and pathologic feature of leukemic T-cell lymphoma,” Cancer, vol. 50, no. 8, pp. 1554–1562, 1982.
[47]
S. Fukumoto, T. Matsumoto, K. Ikeda et al., “Clinical evaluation of calcium metabolism in adult T-cell leukemia/lymphoma,” Archives of Internal Medicine, vol. 148, no. 4, pp. 921–925, 1988.
[48]
T. W. Frick, D. S. Fryd, D. E. R. Sutherland, R. L. Goodale, R. L. Simmons, and J. S. Najarian, “Hypercalcemia associated with pancreatitis and hyperamylasemia in renal transplant recipients. Data from the Minnesota randomized trial of cyclosporine versus antilymphoblast azathioprine,” American Journal of Surgery, vol. 154, no. 5, pp. 487–489, 1987.
[49]
T. R. Kelly, “Relationship of hyperparathyroidism to pancreatitis,” Archives of Surgery, vol. 97, no. 2, pp. 267–274, 1968.
[50]
F. B. Thomas, D. Sinar, J. H. Caldwell, H. S. Mekhjian, and J. M. Falko, “Stimulation of pancreatic secretion of water and electrolytes by furosemide,” Gastroenterology, vol. 73, no. 2, pp. 221–225, 1977.
[51]
L. J. Suva, G. A. Winslow, and R. E. H. Wettenhall, “A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression,” Science, vol. 237, no. 4817, pp. 893–896, 1987.
[52]
G. J. Strewler, P. H. Stern, J. W. Jacobs et al., “Parathyroid hormonelike protein from human renal carcinoma cells. Structural and functional homology with parathyroid hormone,” Journal of Clinical Investigation, vol. 80, no. 6, pp. 1803–1807, 1987.
[53]
W. J. Burtis, T. Wu, and C. Bunch, “Identification of a novel 17,000-dalton parathyroid hormone-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy,” Journal of Biological Chemistry, vol. 262, no. 15, pp. 7151–7156, 1987.
[54]
N. Horiuchi, M. P. Caulfield, J. E. Fisher et al., “Similarity of synthetic peptide from human tumor to parathyroid hormone in vivo and in vitro,” Science, vol. 238, no. 4833, pp. 1566–1568, 1987.
[55]
B. E. Kemp, J. M. Moseley, C. P. Rodda et al., “Parathyroid hormone related protein of malignancy: active synthetic fragments,” Science, vol. 238, no. 4833, pp. 1568–1570, 1987.
[56]
A. F. Stewart, M. Mangin, T. Wu et al., “Synthetic human parathyroid hormone-like protein stimulates bone resorption and causes hypercalcemia in rats,” Journal of Clinical Investigation, vol. 81, no. 2, pp. 596–600, 1988.
[57]
T. J. Rosol and C. C. Capen, “Pathogenesis of humoral hypercalcemia of malignancy,” Domestic Animal Endocrinology, vol. 5, no. 1, pp. 1–21, 1988.
[58]
A. E. Broadus, M. Mangin, K. Ikeda et al., “Humoral hypercalcemia of cancer: identification of a novel parathyroid hormone-like peptide,” The New England Journal of Medicine, vol. 319, no. 9, pp. 556–563, 1988.
[59]
K. Ikeda, R. Okazaki, D. Inoue, H. Ohno, E. Ogata, and T. Matsumoto, “Interleukin-2 increases production and secretion of parathyroid hormone- related peptide by human T cell leukemia virus type I-infected T cells: possible role in hypercalcemia associated with adult T cell leukemia,” Endocrinology, vol. 132, no. 6, pp. 2551–2556, 1993.
[60]
N. Mori, K. Ohsumi, S. Murakami et al., “Enhancing effect of interleukin-2 on production of parathyroid hormone-related protein by adult T-Cell leukemia cells,” Japanese Journal of Cancer Research, vol. 84, no. 4, pp. 425–430, 1993.
[61]
M. Ohmori, M. Nagai, M. Fujita et al., “A novel mature B-cell line (DOBIL-6) producing both parathyroid hormone- related protein and interleukin-6 from a myeloma patient presenting with hypercalcaemia,” British Journal of Haematology, vol. 101, no. 4, pp. 688–693, 1998.
[62]
N. Ota, T. Nakajima, I. Nakazawa et al., “A nucleotide variant in the promoter region of the interleukin-6 gene associated with decreased bone mineral density,” Journal of Human Genetics, vol. 46, no. 5, pp. 267–272, 2001.
[63]
G. Franchini, F. Wong-Staal, and R. C. Gallo, “Human T-cell leukemia virus (HTLV-I) transcripts in fresh and cultured cells of patients with adult T-cell leukemia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 81, no. 19, pp. 6207–6211, 1984.
[64]
T. Kinoshita, M. Shimoyama, K. Tobinai et al., “Detection of mRNA for the tax1/rex1 gene of human T-cell leukemia virus type I in fresh peripheral blood mononuclear cells of adult T-cell leukemia patients and viral carriers by using the polymerase chain reaction,” Proceedings of the National Academy of Sciences of the United States of America, vol. 86, no. 14, pp. 5620–5624, 1989.
[65]
T. Watanabe, K. Yamaguchi, K. Takatsuki, M. Osame, and M. Yoshida, “Constitutive expression of parathyroid hormone-related protein gene in human T cell leukemia virus type 1 (HTLV-1) carriers and adult T cell leukemia patients that can be trans-activated by HTLV-1 tax gene,” Journal of Experimental Medicine, vol. 172, no. 3, pp. 759–765, 1990.
[66]
J. Dittmer, S. D. Gitlin, R. L. Reid, and J. N. Brady, “Transactivation of the P2 promoter of parathyroid hormone-related protein by human T-cell lymphotropic virus type I Tax1: evidence for the involvement of transcription factor Ets1,” Journal of Virology, vol. 67, no. 10, pp. 6087–6095, 1993.
[67]
D. Prager, J. D. Rosenblatt, and E. Ejima, “Hypercalcemia, parathyroid hormone-related protein expression and human T-cell leukemia virus infection,” Leukemia and Lymphoma, vol. 14, no. 5-6, pp. 395–400, 1994.
[68]
A. Takaori-Kondo, K. Imada, I. Yamamoto et al., “Parathyroid hormone-related protein-induced hypercalcemia in SCID mice engrafted with adult T-cell leukemia cells,” Blood, vol. 91, no. 12, pp. 4747–4751, 1998.
[69]
K. Matsuzaki, K. Katayama, Y. Takahashi et al., “Human osteoclast-like cells are formed from peripheral blood mononuclear cells in a coculture with SaOS-2 cells transfected with the parathyroid hormone (PTH)/PTH-related protein receptor gene,” Endocrinology, vol. 140, no. 2, pp. 925–932, 1999.
[70]
K. Yamaguchi, T. Kiyokawa, T. Watanabe et al., “Increased serum levels of C-terminal parathyroid hormone-related protein in different diseases associated with HTLV-1 infection,” Leukemia, vol. 8, no. 10, pp. 1708–1711, 1994.
[71]
C. Menaa, N. Kurihara, and G. D. Roodman, “CFU-GM-derived cells form osteoclasts at a very high efficiency,” Biochemical and Biophysical Research Communications, vol. 267, no. 3, pp. 943–946, 2000.
[72]
F. Arai, T. Miyamoto, O. Ohneda et al., “Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor κB (RANK) receptors,” Journal of Experimental Medicine, vol. 190, no. 12, pp. 1741–1754, 1999.
[73]
D. L. Lacey, E. Timms, H. L. Tan et al., “Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation,” Cell, vol. 93, no. 2, pp. 165–176, 1998.
[74]
M. J. A. T. Suda and N. Takahashi, “Contributions to osteoclast biology from Japan,” Proceedings of the Japan Academy Series B, vol. 84, no. 10, pp. 419–438, 2008.
[75]
J. M. Blair, Y. Zheng, and C. R. Dunstan, “RANK ligand,” International Journal of Biochemistry and Cell Biology, vol. 39, no. 6, pp. 1077–1081, 2007.
[76]
H. Hsu, D. L. Lacey, C. R. Dunstan et al., “Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 7, pp. 3540–3545, 1999.
[77]
D. M. Anderson, E. Maraskovsky, W. L. Billingsley et al., “A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function,” Nature, vol. 390, no. 6656, pp. 175–179, 1997.
[78]
L. C. Hofbauer and M. Schoppet, “Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases,” Journal of the American Medical Association, vol. 292, no. 4, pp. 490–495, 2004.
[79]
H. L. Wright, H. S. McCarthy, J. Middleton, and M. J. Marshall, “RANK, RANKL and osteoprotegerin in bone biology and disease,” Current Reviews in Musculoskeletal Medicine, vol. 2, no. 1, pp. 56–64, 2009.
[80]
E. A. O'Brien, J. H. H. Williams, and M. J. Marshall, “Osteoprotegerin is produced when prostaglandin synthesis is inhibited causing osteoclasts to detach from the surface of mouse parietal bone and attach to the endocranial membrane,” Bone, vol. 28, no. 2, pp. 208–214, 2001.
[81]
W. S. Simonet, D. L. Lacey, C. R. Dunstan et al., “Osteoprotegerin: a novel secreted protein involved in the regulation of bone density,” Cell, vol. 89, no. 2, pp. 309–319, 1997.
[82]
K. M. Woo, Y. Choi, S. H. Ko, J. S. Ko, K. O. Oh, and K. K. Kim, “Osteoprotegerin is present on the membrane of osteoclasts isolated from mouse long bones,” Experimental and Molecular Medicine, vol. 34, no. 5, pp. 347–352, 2002.
[83]
Y. Y. Kong, W. J. Boyle, and J. M. Penninger, “Osteoprotegerin ligand: a regulator of immune responses and bone physiology,” Immunology Today, vol. 21, no. 10, pp. 495–502, 2000.
[84]
B. Bolon, C. Carter, M. Daris et al., “Adenoviral delivery of osteoprotegerin ameliorates bone resorption in a mouse ovariectomy model of osteoporosis,” Molecular Therapy, vol. 3, no. 2, pp. 197–205, 2001.
[85]
T. Kondo, R. Kitazawa, S. Maeda, and S. Kitazawa, “1α,25 dihydroxyvitamin D3 rapidly regulates the mouse osteoprotegerin gene through dual pathways,” Journal of Bone and Mineral Research, vol. 19, no. 9, pp. 1411–1419, 2004.
[86]
T. Watanabe, “HTLV-V-1-associated diseases,” International Journal of Hematology, vol. 66, no. 3, pp. 257–278, 1997.
[87]
Y. Wano, T. Hattori, M. Matsuoka et al., “Interleukin 1 gene expression in adult T cell leukemia,” Journal of Clinical Investigation, vol. 80, no. 3, pp. 911–916, 1987.
[88]
Y. Niitsu, Y. Urushizaki, Y. Koshida et al., “Expression of TGF-beta gene in adult T cell leukemia,” Blood, vol. 71, no. 1, pp. 263–266, 1988.
[89]
S. Honda, K. Yamaguchi, Y. Miyake et al., “Production of parathyroid hormone-related protein in adult T-cell leukemia cells,” Japanese Journal of Cancer Research, vol. 79, no. 12, pp. 1264–1268, 1988.
[90]
S. J. Kim, J. H. Kehrl, J. Burton et al., “Transactivation of the transforming growth factor β1 (TGF-β1) gene by human T lymphotropic virus type 1 Tax: a potential mechanism for the increased production of TGF-β1 in adult T cell leukemia,” Journal of Experimental Medicine, vol. 172, no. 1, pp. 121–129, 1990.
[91]
P. M. Villiger, M. T. Cronin, T. Amenomori, W. Wachsman, and M. Lotz, “IL-6 production by human T lymphocytes. Expression in HTLV-1-infected but not in normal T cells,” Journal of Immunology, vol. 146, no. 2, pp. 550–559, 1991.
[92]
Y. Okada, J. Tsukada, K. Nakano, S. Tonai, S. Mine, and Y. Tanaka, “Macrophage inflammatory protein-1α induces hypercalcemia in adult T-cell leukemia,” Journal of Bone and Mineral Research, vol. 19, no. 7, pp. 1105–1111, 2004.
[93]
M. Matsuoka, “Human T-cell leukemia virus type I and adult T-cell leukemia,” Oncogene, vol. 22, no. 33, pp. 5131–5140, 2003.
[94]
M. Matsuoka and K. T. Jeang, “Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation,” Nature Reviews Cancer, vol. 7, no. 4, pp. 270–280, 2007.
[95]
X. Lianping, T. P. Bushnell, C. Louise et al., “NF-κB p50 and p52 expression is not required for RANK-expressing osteoclast progenitor formation but is essential for RANK- and cytokine-mediated osteoclastogenesis,” Journal of Bone and Mineral Research, vol. 17, no. 7, pp. 1200–1210, 2002.
[96]
M. D. Lairmore, L. Silverman, and L. Ratner, “Animal models for human T-lymphotropic virus type 1 (HTLV-1) infection and transformation,” Oncogene, vol. 24, no. 39, pp. 6005–6015, 2005.
[97]
M. Z. Dewan, K. Terashima, M. Taruishi et al., “Rapid tumor formation of human T-cell leukemia virus type 1-infected cell lines in novel NOD-SCID/γcnull mice: suppression by an inhibitor against NF-κB,” Journal of Virology, vol. 77, no. 9, pp. 5286–5294, 2003.
[98]
Y. Liu, K. Dole, J. R. L. Stanley et al., “Engraftment and tumorigenesis of HTLV-1 transformed T cell lines in SCID/bg and NOD/SCID mice,” Leukemia Research, vol. 26, no. 6, pp. 561–567, 2002.
[99]
T. Ohsugi, K. Yamaguchi, T. Kumasaka et al., “Rapid tumor death model for evaluation of new therapeutic agents for adult T-cell leukemia,” Laboratory Investigation, vol. 84, no. 2, pp. 263–266, 2004.
[100]
V. Richard, M. D. Lairmore, P. L. Green et al., “Humoral hypercalcemia of malignancy: severe combined immunodeficient/beige mouse model of adult T-cell lymphoma independent of human T-cell lymphotropic virus type-1 tax expression,” American Journal of Pathology, vol. 158, no. 6, pp. 2219–2228, 2001.
[101]
Y. Sagara, Y. Inoue, Y. Sagara, and S. Kashiwagi, “Involvement of molecular mimicry between human T-cell leukemia virus type 1 gp46 and osteoprotegerin in induction of hypercalcemia,” Cancer Science, vol. 100, no. 3, pp. 490–496, 2009.
[102]
S. T. Shu, C. K. Martin, N. K. Thudi, W. P. Dirksen, and T. J. Rosol, “Osteolytic bone resorption in adult T-cell leukemia/lymphoma,” Leukemia and Lymphoma, vol. 51, no. 4, pp. 702–714, 2010.
[103]
N. Polakowski, H. Gregory, J. M. Mesnard, and I. Lemasson, “Expression of a protein involved in bone resorption, Dkk1, is activated by HTLV-1 bZIP factor through its activation domain,” Retrovirology, vol. 7, p. 61, 2010.
