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Cancer and Metastasis Reviews

, Volume 25, Issue 4, pp 541–549 | Cite as

The RANK/RANKL/OPG triad in cancer-induced bone diseases

  • William C. Dougall
  • Michelle Chaisson
Article

Abstract

The maintenance of skeletal integrity in a healthy individual requires a balanced regulation of the processes of bone formation, mediated by osteoblasts, and bone resorption, mediated by osteoclasts. This balanced process of bone remodeling becomes co-opted in the skeleton by tumor cells and this dramatically accelerates the process of remodeling and disrupts the normal equilibrium resulting in a spectrum of osteolytic to osteoblastic bone lesions. Certain tumor types, such as breast and prostate, frequently metastasize to the bone. It is now widely understood that the molecular triad—receptor activator of NF-κB ligand (RANKL), its receptor RANK, and the endogenous soluble RANKL inhibitor, osteoprotegerin (OPG)—play direct and essential roles in the formation, function, and survival of osteoclasts. Osteoclastic bone resorption contributes to the majority of skeletal sequelae, or skeletal-related events (SREs), in patients with bone metastases. In addition, osteoclastic bone resorption also contributes to the establishment of tumors in the skeleton. Therefore, blocking osteoclast activity and differentiation via RANKL inhibition may not only provide a beneficial treatment for skeletal complications of malignancy, but may also prevent bone metastases. In this review, we will first describe the operative role of osteoclasts and the RANK/RANKL/OPG triad in the pathophysiology of cancer-induced bone diseases, specifically solid tumor metastases to the bone. Secondly, we will describe a therapeutic approach that specifically targets the RANKL molecule.

Keywords

Receptor activator of NF-κB (RANK) RANKL Osteoprotegerin (OPG) Osteoclasts Bone metastasis 

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References

  1. 1.
    Coleman, R. E. (1997). Skeletal complications of malignancy. Cancer, 80(Suppl 8), 1588–1594.PubMedCrossRefGoogle Scholar
  2. 2.
    Mundy, G. R. (2002). Metastasis to bone: Causes, consequences and therapeutic opportunities. Nature Review Cancer, 2, 584–593.CrossRefGoogle Scholar
  3. 3.
    Roodman, G. D. (2004). Mechanisms of bone metastasis. New England Journal of Medicine, 350, 1655–1664.PubMedCrossRefGoogle Scholar
  4. 4.
    Taube, T., Elomaa, I., Blomqvist, C., Beneton, M. N., & Kanis, J.A. (1994). Histomorphometric evidence for osteoclast-mediated bone resorption in metastatic breast cancer. Bone, 15, 161–166.PubMedCrossRefGoogle Scholar
  5. 5.
    Coleman, R. E. (2001). Metastatic bone disease: Clinical features, pathophysiology and treatment strategies. Cancer Treatment Reviews, 27, 165–176.PubMedCrossRefGoogle Scholar
  6. 6.
    Schwei, M. J., Honore, P., Rogers, S. D., Salak-Johnson, J. L., Finke, M. P., Ramnaraine, M. L., et al. (1999). Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain. Journal of Neuroscience, 19, 10886–10897.PubMedGoogle Scholar
  7. 7.
    Clohisy, D. R., & Mantyh, P. W. (2004). Bone cancer pain and the role of RANKL/OPG. Journal of Musculoskeletal Neuronal Interaction, 4, 293–300.Google Scholar
  8. 8.
    Coleman, R. E., Major, P., Lipton, A., Brown, J. E., Lee, K. A., Smith, M., et al. (2005). Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. Journal of Clinical Oncology, 23, 4925–4935.PubMedCrossRefGoogle Scholar
  9. 9.
    Charhon, S. A., Chapuy, M. C., Delvin, E. E., Valentin-Opran, A., Edouard, C. M., & Meunier, P. J. (1983). Histomorphometric analysis of sclerotic bone metastases from prostatic carcinoma special reference to osteomalacia. Cancer, 51, 918–924.PubMedCrossRefGoogle Scholar
  10. 10.
    Stewart, A. F., Vignery, A., Silverglate, A., Ravin, N. D., LiVolsi, V., Broadus, A. E., et al. (1982). Quantitative bone histomorphometry in humoral hypercalcemia of malignancy: Uncoupling of bone cell activity. Journal of Clinical Endocrinology and Metabolism, 55, 219–227.PubMedCrossRefGoogle Scholar
  11. 11.
    Urwin, G. H., Percival, R. C., Harris, S., Beneton, M. N., Williams, J. L., & Kanis, J. A. (1985). Generalised increase in bone resorption in carcinoma of the prostate. British Journal of Urology, 57, 721–723.PubMedCrossRefGoogle Scholar
  12. 12.
    Chirgwin, J. M., & Guise, T. A. (2000). Molecular mechanisms of tumor–bone interactions in osteolytic metastases. Critical Reviews in Eukaryotic Gene Expression, 10, 159–178.PubMedGoogle Scholar
  13. 13.
    Demers, L. M., Costa, L., & Lipton, A. (2000). Biochemical markers and skeletal metastases. Cancer, 88(Suppl 12), 2919–2926.PubMedCrossRefGoogle Scholar
  14. 14.
    Clarke, N. W., McClure, J., & George, N. J. (1991). Morphometric evidence for bone resorption and replacement in prostate cancer. British Journal of Urology, 68, 74–80.PubMedGoogle Scholar
  15. 15.
    Martin, T. J. (2004). Paracrine regulation of osteoclast formation and activity: Milestones in discovery. Journal of Musculoskeletal Neuronal Interaction, 4, 243–253.Google Scholar
  16. 16.
    Suda, T., Takahashi, N., & Martin T. J. (1992). Modulation of osteoclast differentiation. Endocrine Review, 13, 66–80.CrossRefGoogle Scholar
  17. 17.
    Tsuda, E., Goto, M., Mochizuki, S., Yano, K., Kobayashi, F., Morinaga, T., et al. (1997). Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochemical and Biophysical Research Communications, 234, 137–142.PubMedCrossRefGoogle Scholar
  18. 18.
    Yasuda, H., Shima, N., Nakagawa, N., Mochizuki, S. I., Yano, K., Fujise N., et al. (1998). Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): A mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology, 139, 1329–1337.PubMedCrossRefGoogle Scholar
  19. 19.
    Simonet, W. S., Lacey, D. L., Dunstan, C. R., Kelley, M., Chang, M. S., Luthy, R., et al. (1997). Osteoprotegerin: A novel secreted protein involved in the regulation of bone density. Cell, 89, 309–319.PubMedCrossRefGoogle Scholar
  20. 20.
    Bucay, N., Sarosi, I., Dunstan, C. R., Morony, S., Tarpley, J., Capparelli, C., et al. (1998). Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes and Development, 12, 1260–1268.PubMedGoogle Scholar
  21. 21.
    Anderson, D. M., Maraskovsky, E., Billingsley, W. L., Dougall, W. C., Tometsko, M. E., Roux, E. R., et al. (1997). A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature, 390, 175–179.PubMedCrossRefGoogle Scholar
  22. 22.
    Lacey, D. L., Timms, E., Tan, H. L., Kelley, M. J., Dunstan, C. R., Burgess, T., et al. (1998). Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell, 93, 165–176.PubMedCrossRefGoogle Scholar
  23. 23.
    Lum, L., Wong, B. R., Josien, R., Becherer, J. D., Erdjument-Bromage, H., Schlondorff, J., et al. (1999). 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. Journal of Biological Chemistry, 274, 13613–13618.PubMedCrossRefGoogle Scholar
  24. 24.
    Lynch, C. C., Hikosaka, A., Acuff, H. B., Martin, M. D., Kawai, N., Singh, R. K., et al. (2005). MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell, 7, 485–496.PubMedCrossRefGoogle Scholar
  25. 25.
    Ikeda, T., Kasai, M., Utsuyama, M., & Hirokawa, K. (2001). Determination of three isoforms of the receptor activator of nuclear factor-kappaB ligand and their differential expression in bone and thymus. Endocrinology, 142, 1419–1426.PubMedCrossRefGoogle Scholar
  26. 26.
    Kong, Y. Y., Yoshida, H., Sarosi, I., Tan, H. L., Timms, E., Capparelli, C., et al. (1999). OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature, 397, 315–323.PubMedCrossRefGoogle Scholar
  27. 27.
    Boyle, W. J., Simonet, W. S., & Lacey, D. L. (2003). Osteoclast differentiation and activation. Nature, 423, 337–342.PubMedCrossRefGoogle Scholar
  28. 28.
    Dougall, W. C., Glaccum, M., Charrier, K., Rohrbach, K., Brasel, K., De Smedt, T., et al. (1999). RANK is essential for osteoclast and lymph node development. Genes and Development, 13, 2412–2424.PubMedCrossRefGoogle Scholar
  29. 29.
    Li, J., Sarosi, I., Yan, X. Q., Morony, S., Capparelli, C., Tan, H. L., et al. (2000). RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proceedings of the National Academy of Sciences of the United States of America, 97, 1566–1571.PubMedCrossRefGoogle Scholar
  30. 30.
    Matsuzaki, K., Udagawa, N., Takahashi, N., Yamaguchi, K., Yasuda, H., Shima, N., et al. (1998). Osteoclast differentiation factor (ODF) induces osteoclast-like cell formation in human peripheral blood mononuclear cell cultures. Biochemical and Biophysical Research Communications, 246, 199–204.PubMedCrossRefGoogle Scholar
  31. 31.
    Wei, S., Kitaura, H., Zhou, P., Ross, F. P., & Teitelbaum, S. L. (2005). IL-1 mediates TNF-induced osteoclastogenesis. Journal of Clinical Investigation, 115, 282–290.PubMedCrossRefGoogle Scholar
  32. 32.
    Wada, T., Nakashima, T., Hiroshi, N., & Penninger, J. M. (2006). RANKL–RANK signaling in osteoclastogenesis and bone disease. Trends in Molecular Medicine, 12, 17–25.PubMedCrossRefGoogle Scholar
  33. 33.
    Ohshiba, T., Miyaura, C., Inada, M., & Ito, A. (2003). Role of RANKL induced osteoclast formation and MMP dependent matrix degradation in bone destruction by breast cancer metastasis. British Journal of Cancer, 88, 1318–1326.PubMedCrossRefGoogle Scholar
  34. 34.
    Zhang, J., Lu, Y., Dai, J., Yao, Z., Kitazawa, R., Kitazawa, S., et al. (2004). In vivo real-time imaging of TGF-beta-induced transcriptional activation of the RANK ligand gene promoter in intraosseous prostate cancer. Prostate, 59, 360–369.PubMedCrossRefGoogle Scholar
  35. 35.
    Bendre, M. S., Montague, D. C., Peery, T., Akel, N. S., Gaddy, D., & Suva, L. J. (2003). Interleukin-8 stimulation of osteoclastogenesis and bone resorption is a mechanism for the increased osteolysis of metastatic bone disease. Bone, 33, 28–37.PubMedCrossRefGoogle Scholar
  36. 36.
    Kitazawa, S., & Kitazawa, R. (2002). RANK ligand is a prerequisite for cancer-associated osteolytic lesions. Journal of Pathology, 198, 228–236.PubMedCrossRefGoogle Scholar
  37. 37.
    Brown, J. M., Corey, E., Lee, Z. D., True, L. D., Yun, T. J., Tondravi, M., et al. (2001). Osteoprotegerin and rank ligand expression in prostate cancer. Urology, 57, 611–616.PubMedCrossRefGoogle Scholar
  38. 38.
    Granchi, D., Amato, I., Battistelli, L., Avnet, S., Capaccioli, S., Papucci, L., et al. (2004). In vitro blockade of receptor activator of nuclear factor-kappaB ligand prevents osteoclastogenesis induced by neuroblastoma cells. International Journal of Cancer, 111, 829–838.CrossRefGoogle Scholar
  39. 39.
    Farrugia, A. N., Atkins, G. J., To, L. B., Pan, B., Horvath, N., Kostakis, P., et al. (2003). Receptor activator of nuclear factor-kappaB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo. Cancer Research, 63, 5438–5445.PubMedGoogle Scholar
  40. 40.
    Nosaka, K., Miyamoto, T., Sakai, T., Mitsuya, H., Suda, T., & Matsuoka, M. (2002). Mechanism of hypercalcemia in adult T-cell leukemia: Overexpression of receptor activator of nuclear factor kappaB ligand on adult T-cell leukemia cells. Blood, 99, 634–640.PubMedCrossRefGoogle Scholar
  41. 41.
    Blair, J. M., Zhou, H., Seibel, M. J., & Dunstan, C. R. (2006). Mechanisms of disease: Roles of OPG, RANKL and RANK in the pathophysiology of skeletal metastasis. Nature Clinical Practice Oncology, 3, 41–49.PubMedCrossRefGoogle Scholar
  42. 42.
    Dovio, A., Data, V., & Angeli, A. (2005). Circulating osteoprotegerin and soluble RANKL: Do they have a future in clinical practice? Journal of Endocrinological Investigation, 28(Suppl 10), 14–22.PubMedGoogle Scholar
  43. 43.
    Terpos, E., Szydlo, R., Apperley, J. F., Hatjiharissi, E., Politou, M., Meletis, J., et al. (2003). Soluble receptor activator of nuclear factor kappaB ligand–osteoprotegerin ratio predicts survival in multiple myeloma: Proposal for a novel prognostic index. Blood, 102, 1064–1069.PubMedCrossRefGoogle Scholar
  44. 44.
    Chen, G., Sircar, K., Aprikian, A., Potti, A., Goltzman, D., & Rabbani, S. A. (2006). Expression of RANKL/RANK/OPG in primary and metastatic human prostate cancer as markers of disease stage and functional regulation. Cancer, 107, 289–298.PubMedCrossRefGoogle Scholar
  45. 45.
    Perez-Martinez, F. C., Alonso, V., Sarasa, J. L., Nam-Cha, S. G., Vela-Navarrete, R., Manzarbeitia, F., et al. (2006, June 14). Immunohistochemical analysis of low-grade and high-grade prostate carcinoma: Relative changes of PTHrP and its PTH1 receptor, osteoprotegerin and receptor activator of nuclear factor kb ligand. Journal of Clinical Pathology, epub ahead of print.Google Scholar
  46. 46.
    Leeming, D. J., Koizumi, M., Byrjalsen, I., Li, B., Qvist, P., & Tanko, L. B. (2006). The relative use of eight collagenous and noncollagenous markers for diagnosis of skeletal metastases in breast, prostate, or lung cancer patients. Cancer Epidemiology, Biomarkers and Prevention, 15, 32–38.PubMedCrossRefGoogle Scholar
  47. 47.
    Jung, K., Stephan, C., Semjonow, A., Lein, M., Schnorr, D., & Loening, S. A. (2003). Serum osteoprotegerin and receptor activator of nuclear factor-kappa B ligand as indicators of disturbed osteoclastogenesis in patients with prostate cancer. Journal of Urology, 170, 2302–2305.PubMedCrossRefGoogle Scholar
  48. 48.
    Holen, I., Cross, S. S., Neville-Webbe, H. L., Cross, N. A., Balasubramanian, S. P., Croucher P. I., et al. (2005). Osteoprotegerin (OPG) expression by breast cancer cells in vitro and breast tumours in vivo—a role in tumour cell survival? Breast Cancer Research and Treatment, 92, 207–215.PubMedCrossRefGoogle Scholar
  49. 49.
    Holen, I., Croucher, P. I., Hamdy, F. C., & Eaton, C. L. (2002). Osteoprotegerin (OPG) is a survival factor for human prostate cancer cells. Cancer Research, 62, 1619–1623.PubMedGoogle Scholar
  50. 50.
    Van Poznak, C., Cross, S. S., Saggese, M., Hudis, C., Panageas, K. S., Norton, L., et al. (2006). Expression of osteoprotegerin (OPG), TNF related apoptosis inducing ligand (TRAIL), and receptor activator of nuclear factor {kappa}B ligand (RANKL) in human breast tumours. Journal of Clinical Pathology, 59, 56–63.PubMedCrossRefGoogle Scholar
  51. 51.
    Horwood, N. J., Elliott, J., Martin, T. J., & Gillespie, M. T. (1998). Osteotropic agents regulate the expression of osteoclast differentiation factor and osteoprotegerin in osteoblastic stromal cells. Endocrinology, 139, 4743–4746.PubMedCrossRefGoogle Scholar
  52. 52.
    Lee, S. K., & Lorenzo, J. A. (1999). Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: Correlation with osteoclast-like cell formation. Endocrinology, 140, 3552–3561.PubMedCrossRefGoogle Scholar
  53. 53.
    Thomas, R. J., Guise, T. A., Yin, J. J., Elliott, J., Horwood, N. J., Martin, T. J., et al. (1999). Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology, 140, 4451–4458.PubMedCrossRefGoogle Scholar
  54. 54.
    Capparelli, C., Kostenuik, P. J., Morony, S., Starnes, C., Weimann, B., Van, G., et al. (2000). Osteoprotegerin prevents and reverses hypercalcemia in a murine model of humoral hypercalcemia of malignancy. Cancer Research, 60, 783–787.PubMedGoogle Scholar
  55. 55.
    Oyajobi, B. O., Anderson, D. M., Traianedes, K., Williams, P. J., Yoneda, T., & Mundy, G. R. (2001). Therapeutic efficacy of a soluble receptor activator of nuclear factor kappaB–IgG Fc fusion protein in suppressing bone resorption and hypercalcemia in a model of humoral hypercalcemia of malignancy. Cancer Research, 61, 2572–2578.PubMedGoogle Scholar
  56. 56.
    Akatsu, T., Murakami, T., Nishikawa, M., Ono, K., Shinomiya, N., Tsuda, E., et al. (1998). Osteoclastogenesis inhibitory factor suppresses osteoclast survival by interfering in the interaction of stromal cells with osteoclast. Biochemical and Biophysical Research Communications, 250, 229–234.PubMedCrossRefGoogle Scholar
  57. 57.
    Morony, S., Warmington, K., Adamu, S., Asuncion, F., Geng, Z., Grisanti, M., et al. (2005). The RANKL inhibitor osteoprotegerin (OPG) causes greater suppression of bone resorption and hypercalcemia compared to bisphosphonates in two models of humoral hypercalcemia of malignancy. Endocrinology, 146, 3235–3243.PubMedCrossRefGoogle Scholar
  58. 58.
    Catrina, A. I., Klint, E. A., Ernestam, S., Catrina, S. B., Makrygiannakis, D., Botusan, I. R., et al. (2006). Anti-tumor necrosis factor therapy increases synovial osteoprotegerin expression in rheumatoid arthritis. Arthritis and Rheumatism, 54, 76–81.PubMedCrossRefGoogle Scholar
  59. 59.
    Morony, S., Bolon, B., Carter, C., Geng, Z., Daris, M., Kostenuik, P., et al (2003). Delivery of osteoprotegerin (OPG) using an adeno-associated virus (AAV) gene therapy vector reverse established osteopenia in ovariectomized (OVX) mice. Journal of Bone and Mineral Research, 18(Suppl 2).Google Scholar
  60. 60.
    Morony, S., Capparelli, C., Sarosi, I., Lacey, D. L., Dunstan, C. R., & Kostenuik, P. J. (2001). Osteoprotegerin inhibits osteolysis and decreases skeletal tumor burden in syngeneic and nude mouse models of experimental bone metastasis. Cancer Research, 61, 4432–4436.PubMedGoogle Scholar
  61. 61.
    Whang, P. G., Schwarz, E. M., Gamradt S. C., Dougall, W. C., & Lieberman, J. R. (2005). The effects of RANK blockade and osteoclast depletion in a model of pure osteoblastic prostate cancer metastasis in bone. Journal of Orthopaedic Research, 23, 1475–1483.PubMedGoogle Scholar
  62. 62.
    Miller, R., Jones, J., Tometsko, M., Armstrong, A., Zhang, N., Leal, J., et al. (2005). Antitumor efficacy of the RANK ligand inhibitor OPG-Fc in the MDA-231 breast cancer and PC3 prostate cancer experimental osteolytic metastases models. Journal of Bone and Mineral Research, 20(Suppl 1), S117.Google Scholar
  63. 63.
    Tannehill-Gregg, S. H., Levine, A. L., Nadella, M. V., Iguchi, H., & Rosol, T. J. (2006, May 20). The effect of zoledronic acid and osteoprotegerin on growth of human lung cancer in the tibias of nude mice. Clinical and Experimental Metastasis, epub ahead of print.Google Scholar
  64. 64.
    Yonou, H., Kanomata, N., Goya, M., Kamijo, T., Yokose, T., Hasebe, T., et al. (2003). Osteoprotegerin/osteoclastogenesis inhibitory factor decreases human prostate cancer burden in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice. Cancer Research, 63, 2096–2102.PubMedGoogle Scholar
  65. 65.
    Zhang, J., Dai, J., Qi, Y., Lin, D. L., Smith, P., Strayhorn, C., et al. (2001). Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone. Journal of Clinical Investigation, 107, 1235–1244.PubMedCrossRefGoogle Scholar
  66. 66.
    Zhang, J., Dai, J., Yao, Z., Lu, Y., Dougall, W., & Keller, E. T. (2003). Soluble receptor activator of nuclear factor kappaB Fc diminishes prostate cancer progression in bone. Cancer Research, 63, 7883–7890.PubMedGoogle Scholar
  67. 67.
    Guise, T. A. (2000). Molecular mechanisms of osteolytic bone metastases. Cancer, 88(Suppl 12), 2892–2898.PubMedCrossRefGoogle Scholar
  68. 68.
    Mundy, G. R. (2002). Metastasis to bone: Causes, consequences and therapeutic opportunities. Nature Reviews. Cancer, 2, 584–593.PubMedCrossRefGoogle Scholar
  69. 69.
    Kiefer, J. A., Vessella, R. L., Quinn, J. E., Odman, A. M., Zhang, J., Keller, E. T., et al. (2004). The effect of osteoprotegerin administration on the intra-tibial growth of the osteoblastic LuCaP 23.1 prostate cancer xenograft. Clinical and Experimental Metastasis, 21, 381–387.PubMedCrossRefGoogle Scholar
  70. 70.
    Corey, E., Brown, L. G., Kiefer, J. A., Quinn, J. E., Pitts, T. E., Blair, J. M., et al. (2005). Osteoprotegerin in prostate cancer bone metastasis. Cancer Research, 65, 1710–1718.PubMedCrossRefGoogle Scholar
  71. 71.
    Atkinson, J. E., Cranmer, P., Mohr, S., Niehaus, M., Jerome, C. P., Cosenza, M. E., et al. (2003). Bone mineral density is increased following monthly administration of AMG 162 in cynomolgus monkeys. Journal of Bone and Mineral Research, 18(Suppl 2), S96.Google Scholar
  72. 72.
    Body, J. J., Coleman, R. E., Lipton, A., Murphy, R., Holloway, D. L., Bekker, P. J., et al. (2004). Rapid, profound, and prolonged suppression of bone turnover with a single SC dose of AMG 162 in women with breast cancer metastatic to bone. Journal of Bone and Mineral Research, 19, 1593.Google Scholar
  73. 73.
    Peterson, M. C., Martin, S. W., Stouch, B. J., Chen, D., Holloway, D. L., Body, J.-J., et al. (2004). Pharmacokinetics (PK) and pharmacodynamics (PD) of AMG 162, a fully human monoclonal antibody to receptor activator of NF kappa B ligand (RANKL), following a single subcutaneous dose to patients with cancer-related bone lesions. Journal of Clinical Oncology, 22(Suppl 14), 8106.Google Scholar
  74. 74.
    McClung, M. R., Lewiecki, E. M., Cohen, S. B., Bolognese, M. A., Woodson, G. C., Moffett, A. H., et al. (2006). Denosumab in postmenopausal women with low bone mineral density. New England Journal of Medicine, 354, 821–831.PubMedCrossRefGoogle Scholar
  75. 75.
    Tometsko, M., Armstrong, A., Miller, R., Jones, J., Chaisson, M., Branstetter, D., et al. (2004). RANK ligand directly induces osteoclastogenic, angiogenic, chemoattractive and invasive factors on RANK-expressing human cancer cells MDA-MB-231 and PC3. Journal of Bone and Mineral Research, 19(Suppl 1), S25.Google Scholar
  76. 76.
    Jones, D. H., Nakashima, T., Sanchez, O. H., Kozieradzki, I., Komarova, S. V., Sarosi, I., et al. (2006). Regulation of cancer cell migration and bone metastasis by RANKL. Nature, 440, 692–696.PubMedCrossRefGoogle Scholar
  77. 77.
    Fata, J. E., Kong, Y. Y., Li, J., Sasaki, T., Irie-Sasaki, J., Moorehead, R. A., et al. (2000). The osteoclast differentiation factor osteoprotegerin–ligand is essential for mammary gland development. Cell, 103, 41–50.PubMedCrossRefGoogle Scholar
  78. 78.
    Cao, Y., Bonizzi, G., Seagroves, T. N., Greten, F. R., Johnson, R., Schmidt, E. V., et al. (2001). IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cell, 107, 763–775.PubMedCrossRefGoogle Scholar
  79. 79.
    Landis, M. W., Pawlyk, B. S., Li, T., Sicinski, P., & Hinds, P. W. (2006). Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell, 9, 13–22.PubMedCrossRefGoogle Scholar
  80. 80.
    Bhatia, P., Sanders, M. M., Hansen, M. F. (2005). Expression of receptor activator of nuclear factor-kappaB is inversely correlated with metastatic phenotype in breast carcinoma. Clinical Cancer Research, 11, 162–165.PubMedGoogle Scholar
  81. 81.
    Roux, S., Amazit, L., Meduri, G., Guiochon-Mantel, A., Milgrom, E., Mariette, X. (2002). RANK (receptor activator of nuclear factor kappa B) and RANK ligand are expressed in giant cell tumors of bone. American Journal of Clinical Pathology, 117, 210–216.PubMedCrossRefGoogle Scholar
  82. 82.
    Fiumara, P., Snell, V., Li, Y., Mukhopadhyay, A., Younes, M., Gillenwater, A. M., Cabanillas, F., Aggarwal, B. B., Younes, A. (2001). Functional expression of receptor activator of nuclear factor kappaB in Hodgkin disease cell lines. Blood, 98, 2784–2790.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  1. 1.Department of Cancer BiologyAmgen WashingtonSeattleUSA

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