Cancer and Metastasis Reviews

, Volume 31, Issue 3–4, pp 569–578 | Cite as

Genes associate with abnormal bone cell activity in bone metastasis



Bone is one of the most frequent sites of metastasis in patients with malignancies. Up to 90 % of patients with multiple myeloma, and 60 % to 75 % patients with prostate cancer and breast cancer develop bone metastasis at the later stages of their diseases. Bone metastases are responsible for tremendous morbidity in patients with cancer, including severe bone pain, pathologic fractures, spinal cord and nerve compression syndromes, life-threatening hypercalcemia, and increased mortality. Multiple factors produced by tumor cells or produced by the bone marrow microenvironment in response to tumor cells play important roles in activation of osteoclastic bone resorption and modulation of osteoblastic activity in patients with bone metastasis. In this chapter, we will review the genes that play important roles in bone destruction, tumor growth, and osteoblast activity in bone metastasis and discuss the potential therapies targeting the products of these genes to block both bone destruction and tumor growth.


Bone metastasis Myeloma Microenvironment Osteoclasts Osteoblasts 



This work was supported in part by research funds from the Multiple Myeloma Research Foundation, the Veterans Administration and the National Institutes of Health. I want to thank Susan Johnston for her help in producing the manuscript.


  1. 1.
    Coleman, R. E. (2000). Management of bone metastases. The Oncologist, 5(6), 463–470.PubMedCrossRefGoogle Scholar
  2. 2.
    Coleman, R. E. (2001). Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treatment Reviews, 27, 165–176.PubMedCrossRefGoogle Scholar
  3. 3.
    Mundy, G. R. (2002). Metastasis to bone: causes, consequences and therapeutic opportunities. Nature Reviews Cancer, 2, 584–593.PubMedCrossRefGoogle Scholar
  4. 4.
    Lipton, A. (2004). Pathophysiology of bone metastases: how this knowledge may lead to therapeutic intervention. Journal of Supportive Oncology, 2(3), 205–213. discussion 213–214, 216–217, 219–220.PubMedGoogle Scholar
  5. 5.
    Rosen, L. S., Gordon, D., Kaminski, M., Howell, A., Belch, A., Mackey, J., Apffelstaedt, J., Hussein, M. A., Coleman, R. E., Reitsma, D. J., Chen, B. L., & Seaman, J. J. (2003). Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer, 98(8), 1735–1744.PubMedCrossRefGoogle Scholar
  6. 6.
    Chirgwin, J. M., & Guise, T. A. (2000). Molecular mechanisms of tumor–bone interactions in osteolytic metastases. Critical Reviews in Eukaryotic Gene Expression, 10(2), 159–178.PubMedCrossRefGoogle Scholar
  7. 7.
    Taube, T., Elomaa, I., Blomqvist, C., et al. (1994). Histomorphometric evidence for osteoclast-mediated bone resorption in metastatic breast cancer. Bone, 15(2), 161–166.PubMedCrossRefGoogle Scholar
  8. 8.
    Boyde A, Maconnachie E, Reid SA, et al. (1986). Scanning electron microscopy in bone pathology: review of methods, potential and applications. Scan Electron Microsc (Pt 4), 1537–1554.Google Scholar
  9. 9.
    Fowler, J. A., Edwards, C. M., & Croucher, P. I. (2011). Tumor-host cell interactions in the bone disease of myeloma. Molecular mechanisms of breast cancer metastases to bone. Bone, 48(1), 121–128.PubMedCrossRefGoogle Scholar
  10. 10.
    Guise, T. A., Kozlow, W. M., Heras-Herzig, A., Padalecki, S. S., Yin, J. J., & Chirgwin, J. M. (2005). Molecular mechanisms of breast cancer metastases to bone. Clinical Breast Cancer, 5(Suppl(2)), S46–S53.PubMedCrossRefGoogle Scholar
  11. 11.
    Roodman, G. D. (2004). Mechanisms of bone metastasis. The New England Journal of Medicine, 350(16), 1655–1664.PubMedCrossRefGoogle Scholar
  12. 12.
    Cackowski, F. C., Anderson, J. L., Patrene, K. D., Choksi, R. J., Shapiro, S. D., Windle, J. J., Blair, H. C., & Roodman, G. D. (2010). Osteoclasts are important for bone angiogenesis. Blood, 115(1), 140–149.PubMedCrossRefGoogle Scholar
  13. 13.
    Lacey, D. L., Timms, E., Tan, H. L., et al. (1998). Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell, 93(2), 165–176.PubMedCrossRefGoogle Scholar
  14. 14.
    Dougall, W. C., Glaccum, M., Charrier, K., et al. (1999). RANK is essential for osteoclast and lymph node development. Genes & Development, 13(18), 2412–2424.CrossRefGoogle Scholar
  15. 15.
    Sezer, O., Heider, U., Jakob, C., et al. (2002). Human bone marrow myeloma cells express RANKL. Journal of Clinical Oncology, 20(1), 353–354.PubMedGoogle Scholar
  16. 16.
    Huang, L., Cheng, Y. Y., Chow, L. T. C., Zheng, M. H., & Kumta, S. M. (2002). Tumour cells produce receptor activator of NF-κB ligand (RANKL) in skeletal metastases. J Clin Path, 55(11), 877–878.PubMedCrossRefGoogle Scholar
  17. 17.
    Hofbauer, L. C., Khosla, S., Dunstan, C. R., Lacey, D. L., Boyle, W. J., & Riggs, B. L. (2000). The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. Journal of Bone and Mineral Research, 15(1), 2–12.PubMedCrossRefGoogle Scholar
  18. 18.
    Fuller, K., Wong, B., Fox, S., Choi, Y., & Chambers, T. J. (1998). TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. The Journal of Experimental Medicine, 188(5), 997–1001.PubMedCrossRefGoogle Scholar
  19. 19.
    Roodman, G. D. (1999). Cell biology of the osteoclast. Experimental Hematology, 27(8), 1229–1241.PubMedCrossRefGoogle Scholar
  20. 20.
    Tsukii, K., Shima, N., Mochizuki, S., et al. (1998). Osteoclast differentiation factor mediates an essential signal for bone resorption induced by 1 alpha, 25-dihydroxyvitamin D3, prostaglandin E2, or parathyroid hormone in the microenvironment of bone. Biochemical and Biophysical Research Communications, 246(2), 337–341.PubMedCrossRefGoogle Scholar
  21. 21.
    Hofbauer, L. C., Neubauer, A., & Heufelder, A. E. (2001). Receptor activator of nuclear factor-kappaB ligand and osteoprotegerin: potential implications for the pathogenesis and treatment of malignant bone diseases. Cancer, 92(3), 460–470.PubMedCrossRefGoogle Scholar
  22. 22.
    Feng, X. (2005). RANKing intracellular signaling in osteoclasts. IUBMB Life, 57(6), 389–395.PubMedCrossRefGoogle Scholar
  23. 23.
    Santos, V. R., Lima, J. A., Gonçalves, T. E., Bastos, M. F., Figueiredo, L. C., Shibli, J. A., & Duarte, P. M. (2010). Receptor activator of nuclear factor-kappa B ligand/osteoprotegerin ratio in sites of chronic periodontitis of subjects with poorly and well-controlled type 2 diabetes. Journal of Periodontology, 81(10), 1455–1465.PubMedCrossRefGoogle Scholar
  24. 24.
    Goranova-Marinova, V., Goranov, S., Pavlov, P., & Tzvetkova, T. (2007). Serum levels of OPG, RANKL and RANKL/OPG ratio in newly-diagnosed patients with multiple myeloma. Clinical Correlations. Haematologica, 92(7), 1000–1001.CrossRefGoogle Scholar
  25. 25.
    Terpos, E., Szydlo, R., Apperley, J. F., Hatjiharissi, E., Politou, M., Meletis, J., Viniou, N., Yataganas, X., Goldman, J. M., & Rahemtulla, A. (2003). Soluble receptor activator of nuclear factor KB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index. Blood, 102(3), 1064–1069.Google Scholar
  26. 26.
    Canon, J., Bryant, R., Roudier, M., Osgood, T., Jones, J., Miller, R., Coxon, A., Radinsky, R., & Dougall, W. C. (2010). Inhibition of RANKL increases the anti-tumor effect of the EGFR inhibitor panitumumab in a murine model of bone metastasis. Bone, 46(6), 1613–1619.PubMedCrossRefGoogle Scholar
  27. 27.
    Canon, J. R., Roudier, M., Bryant, R., Morony, S., Stolina, M., Kostenuik, P. J., & Dougall, W. C. (2008). Inhibition of RANKL blocks skeletal tumor progression and improves survival in a mouse model of breast cancer bone metastasis. Clinical & Experimental Metastasis, 25(2), 119–129.CrossRefGoogle Scholar
  28. 28.
    Tannehill-Gregg, S. H., Levine, A. L., Nadella, M. V., Iguchi, H., & Rosol, T. J. (2006). The effect of zoledronic acid and osteoprotegerin on growth of human lung cancer in the tibias of nude mice. Clinical & Experimental Metastasis, 23(1), 19–31.CrossRefGoogle Scholar
  29. 29.
    Gonzalez-Suarez, E., Jacob, A. P., Jones, J., Miller, R., Roudier-Meyer, M. P., Erwert, R., Pinkas, J., Branstetter, D., & Dougall, W. C. (2010). RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature, 468(7320), 103–107.PubMedCrossRefGoogle Scholar
  30. 30.
    Azim, H., Michiels, S., Bedard, P. L., Singhal, S. K., Criscitiello, C., Ignatiadis, M., Haibe-Kains, B., Piccart, M. J., Sotiriou, C., & Loi, S. (2012). Elucidating prognosis and biology of breast cancer arising in young women using gene expression profiling. Clin Cancer Res, 18, 1341–1351.PubMedCrossRefGoogle Scholar
  31. 31.
    Tang, Z. N., Zhang, F., Tang, P., Qi, X. W., & Jiang, J. (2011). RANKL-induced migration of MDA-MB-231 human breast cancer cells via Src and MAPK activation. Oncology Reports, 26(5), 1243–1250. doi: 10.3892/or.11.1368.PubMedGoogle Scholar
  32. 32.
    Jones, D. H., Nakashima, T., Sanchez, O. H., Kozieradzki, I., Komarova, S. V., Sarosi, I., Morony, S., Rubin, E., Sarao, R., Hojilla, C. V., Komnenovic, V., Kong, Y. Y., Schreiber, M., Dixon, S. J., Sims, S. M., Khokha, R., Wada, T., & Penninger, J. M. (2006). Regulation of cancer cell migration and bone metastasis by RANKL. Nature, 440(7084), 692–696.PubMedCrossRefGoogle Scholar
  33. 33.
    Stopeck, A. T., Lipton, A., Body, J. J., Steger, G. G., Tonkin, K., de Boer, R. H., Lichinitser, M., Fujiwara, Y., Yardley, D. A., Viniega, M., Fan, M., Jiang, Q., Dansey, R., Jun, S., & Braun, A. (2010). Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized double-blind study. Journal of Clinical Oncology, 28(35), 5123–5129.CrossRefGoogle Scholar
  34. 34.
    Fizazi, K., Carducci, M., Smith, M., Damião, R., Brown, J., Karsh, L., Milecki, P., Shore, N., Rader, M., Wang, H., Jiang, Q., Tadros, S., Dansey, R., & Goessl, C. (2011). Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomized, double-blind study. Lancet, 337(9768), 813–822.CrossRefGoogle Scholar
  35. 35.
    Henry, D. H., Costa, L., Goldwasser, F., Hirsh, V., Hungria, V., Prausova, J., Scagliotti, G. V., Sleeboom, H., Spencer, A., Vadhan-Raj, S., von Moos, R., Willenbacher, W., Woll, P. J., Wang, J., Jiang, Q., Jun, S., Dansey, R., & Yeh, H. (2011). Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. Journal of Clinical Oncology, 29(9), 1125–1132.PubMedCrossRefGoogle Scholar
  36. 36.
    Choi, S. J., Cruz, J. C., Craig, F., et al. (2000). Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma. Blood, 96(2), 671–675.PubMedGoogle Scholar
  37. 37.
    Han, J. H., Choi, S. J., Kurihara, N., et al. (2001). Macrophage inflammatory protein-1alpha is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor kappaB ligand. Blood, 97(11), 3349–3353.PubMedCrossRefGoogle Scholar
  38. 38.
    Choi, S. J., Oba, Y., Gazitt, Y., et al. (2001). Antisense inhibition of macrophage inflammatory protein 1-alpha blocks bone destruction in a model of myeloma bone disease. The Journal of Clinical Investigation, 108(12), 1833–1841.PubMedGoogle Scholar
  39. 39.
    Oyajobi, B. O., Franchin, G., Williams, P. J., et al. (2003). Dual effects of macrophage inflammatory protein-1alpha on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease. Blood, 102(1), 311–319.PubMedCrossRefGoogle Scholar
  40. 40.
    Vallet, S., Raje, N., Ishitsuka, K., Hideshima, T., Podar, K., Chhetri, S., Pozzi, S., Breitkreutz, I., Kiziltepe, T., Yasui, H., Ocio, E. M., Shiraishi, N., Jin, J., Okawa, Y., Ikeda, H., Mukherjee, S., Vaghela, N., Cirstea, D., Ladetto, M., Boccadoro, M., & Anderson, K. C. (2007). MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts. Blood, 110(10), 3744–3752.PubMedCrossRefGoogle Scholar
  41. 41.
    Oba, Y., Lee, J. W., Ehrlich, L. A., Chung, H. Y., Jelinek, D. F., Callander, N. S., Horuk, R., Choi, S. J., & Roodman, G. D. (2005). MIP-1alpha utilizes both CCR1 and CCR5 to induce osteoclast formation and increase adhesion of myeloma cells to marrow stromal cells. Experimental Hematology, 33(3), 272–278.PubMedCrossRefGoogle Scholar
  42. 42.
    Lentzsch, S., Chatterjee, M., Gries, M., Bommert, K., Gollasch, H., Dörken, B., & Bargou. (2004). RC PI3-K/AKT/FKHR and MAPK signaling cascades are redundantly stimulated by a variety of cytokines and contribute independently to proliferation and survival of multiple myeloma cells. Leukemia, 18(11), 1883–1890.PubMedCrossRefGoogle Scholar
  43. 43.
    Roussou, M., Tasidou, A., Dimopoulos, M. A., Kastritis, E., Migkou, M., Christoulas, D., Gavriatopoulou, M., Zagouri, F., Matsouka, C., Anagnostou, D., & Terpos, E. (2009). Increased expression of macrophage inflammatory protein-1alpha on trephine biopsies correlates with extensive bone disease, increased angiogenesis and advanced stage in newly diagnosed patients with multiple myeloma. Leukemia, 23(11), 2177–2181.PubMedCrossRefGoogle Scholar
  44. 44.
    Terpos, E., Politou, M., Szydlo, R., Goldman, J. M., Apperley, J. F., & Rahemtulla. (2003). A Serum levels of macrophage inflammatory protein-1 alpha (MIP-1alpha) correlate with the extent of bone disease and survival in patients with multiple myeloma. British Journal of Haematology, 123(1), 106–109.PubMedCrossRefGoogle Scholar
  45. 45.
    Cross, N. A., Hillman, L. S., & Forte, L. R. (1998). The effects of calcium supplementation, duration of lactation, and time of day on concentrations of parathyroid hormone-related protein in human milk: a pilot study. Journal of Human Lactation, 14(2), 111–117.PubMedCrossRefGoogle Scholar
  46. 46.
    Guise, T. A. (2000). Molecular mechanisms of osteolytic bone metastases. Cancer, 88(12 Suppl), 2892–2898.PubMedCrossRefGoogle Scholar
  47. 47.
    Kremer, R., Li, J., Camirand, A., & Karaplis, A. C. (2011). Parathyroid hormone related protein (PTHrP) in tumor progression. Advances in Experimental Medicine and Biology, 720, 145–160.PubMedCrossRefGoogle Scholar
  48. 48.
    Yin, J. J., Selander, K., Chirgwin, J. M., Dallas, M., Grubbs, B. G., Wieser, R., Massagué, J., Mundy, G. R., & Guise, T. A. (1999). TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. The Journal of Clinical Investigation, 103(2), 197–206.PubMedCrossRefGoogle Scholar
  49. 49.
    Guise, T. A., Yin, J. J., Taylor, S. D., Kumagai, Y., Dallas, M., Boyce, B. F., Yoneda, T., & Mundy, G. R. (1996). Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. The Journal of Clinical Investigation, 98(7), 1544–1549.PubMedCrossRefGoogle Scholar
  50. 50.
    Tan, A. R., Alexe, G., & Reiss, M. (2008). Transforming growth factor-beta signaling: emerging stem cell target in metastatic breast cancer? Breast Cancer Research and Treatment, 115(3), 453–495.PubMedCrossRefGoogle Scholar
  51. 51.
    Jung, Y., Wang, J., Song, J., et al. (2007). Annexin II expressed by osteoblasts andendothelial cells regulates stem cell adhesion, homing, and engraftment following transplantation. Blood, 110(1), 82–90.PubMedCrossRefGoogle Scholar
  52. 52.
    Rescher, U., & Gerke, V. (2004). Annexins-unique membrane binding proteins with diverse functions. Journal of Cell Science, 117(Pt 13), 2631–2639.PubMedCrossRefGoogle Scholar
  53. 53.
    Waisman, D. M. (1995). Annexin II tetramer: structure and function. Mol Cell Biochem, 149–150, 301–322.PubMedCrossRefGoogle Scholar
  54. 54.
    Lu, G., Maeda, H., Reddy, S. V., et al. (2006). Cloning and characterization of the annexin II receptor on human marrow stromal cells. Journal of Biological Chemistry, 281(41), 30542–30550.PubMedCrossRefGoogle Scholar
  55. 55.
    Shiozawa, Y., Havens, A. M., Jung, Y., et al. (2008). Annexin II/Annexin II receptor axis regulates adhesion, migration, homing, and growth of prostate cancer. Journal of Cellular Biochemistry, 105(2), 370–380.PubMedCrossRefGoogle Scholar
  56. 56.
    Li, F., Chung, H., Reddy, S. V., et al. (2005). Annexin II stimulates RANKL expression through MAPK. Journal of Bone and Mineral Research, 20(7), 1161–1167.PubMedCrossRefGoogle Scholar
  57. 57.
    Takahashi, S., Reddy, S. V., Chirgwin, J. M., et al. (1994). Cloning and identification of annexin II as an autocrine/paracrine factor that increases osteoclast formation and bone resorption. Journal of Biological Chemistry, 269(46), 28696–28701.PubMedGoogle Scholar
  58. 58.
    Claudio, J. O., Masih-Khan, E., Tang, H., et al. (2002). A molecular compendium of genes expressed in multiple myeloma. Blood, 100(6), 2175–2186.PubMedCrossRefGoogle Scholar
  59. 59.
    Bao, H., Jiang, M., Zhu, M., Sheng, F., Ruan, J., & Ruan, C. (2009). Overexpression of Annexin II affects the proliferation, apoptosis, invasion and production of proangiogenic factors in multiple myeloma. International Journal of Hematology, 90(2), 177–185.PubMedCrossRefGoogle Scholar
  60. 60.
    D’Souza, S., Kurihara, N., Shiozawa, Y., Joseph, J., Taichman, R., Galson, D. L., & Roodman, G. D. (2012). Annexin II interactions with the annexin II receptor enhance multiple myeloma cell adhesion and growth in the bone marrow microenvironment. Blood, 119, 1888–1896.PubMedCrossRefGoogle Scholar
  61. 61.
    Lee, J. W., Chung, H. Y., Ehrlich, L. A., et al. (2004). IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells. Blood, 103(6), 2308–2315.PubMedCrossRefGoogle Scholar
  62. 62.
    Rebecca Silbermann, Marina Bolzoni, Paola Storti, Benedetta Dalla Palma, Sabrina Bonomini, Judy Anderson, G. David Roodman, and Nicola Giuliani. (2011). Bone marrow monocyte/macrophage derived activin A mediates the osteoclastogenic effects of IL-3 in myeloma. Blood (ASH Annual Meeting Abstracts) 118: 3933.Google Scholar
  63. 63.
    Cheung, W. C., & Van Ness, B. (2002). Distinct IL-6 signal transduction leads to growth arrest and death in B cells or growth promotion and cell survival in myeloma cells. Leukemia, 16(6), 1182–1188.PubMedCrossRefGoogle Scholar
  64. 64.
    de la Mata, J., Uy, H. L., Guise, T. A., Story, B., Boyce, B. F., Mundy, G. R., & Roodman, G. D. (1995). Interleukin-6 enhances hypercalcemia and bone resorption mediated by parathyroid hormone-related protein in vivo. The Journal of Clinical Investigation, 95(6), 2846–2852.PubMedCrossRefGoogle Scholar
  65. 65.
    Gupta, D., Treon, S. P., Shima, Y., Hideshima, T., Podar, K., Tai, Y. T., Lin, B., Lentzsch, S., Davies, F. E., Chauhan, D., Schlossman, R. L., Richardson, P., Ralph, P., Wu, L., Payvandi, F., Muller, G., Stirling, D. I., & Anderson, K. C. (2001). Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia, 15(12), 1950–1961.PubMedCrossRefGoogle Scholar
  66. 66.
    Riancho, J. A., & Mundy, G. R. (1995). The role of cytokines and growth factors as mediators of the effects of systemic hormones at the bone local level. Critical Reviews in Eukaryotic Gene Expression, 5(3–4), 193–217.PubMedCrossRefGoogle Scholar
  67. 67.
    Raje, N., & Roodman, G. D. (2011). Advances in the biology and treatment of bone disease in multiple myeloma. Clinical Cancer Research, 17(6), 1278–1286.PubMedCrossRefGoogle Scholar
  68. 68.
    Li, X., Pennisi, A., & Yaccoby, S. (2008). Role of decorin in the antimyeloma effects of osteoblasts. Blood, 112(1), 159–168.PubMedCrossRefGoogle Scholar
  69. 69.
    Yang, X., & Karsenty, G. (2002). Transcription factors in bone: developmental and pathological aspects. Trends in Molecular Medicine, 8, 340.PubMedCrossRefGoogle Scholar
  70. 70.
    Roodman, G. D. (2011). Osteoblast function in myeloma. Bone, 48(1), 135–140.PubMedCrossRefGoogle Scholar
  71. 71.
    Tian, E., Zhan, F., Walker, R., et al. (2003). The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. The New England Journal of Medicine, 349(26), 2483–2494.PubMedCrossRefGoogle Scholar
  72. 72.
    Yaccoby, S., Ling, W., Zhan, F., Walker, R., Barlogie, B., & Shaughnessy, J. D., Jr. (2007). Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood, 109(5), 2106–2111.PubMedCrossRefGoogle Scholar
  73. 73.
    Fulciniti, M., Tassone, P., Hideshima, T., et al. (2009). Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood, 114(2), 371–379.PubMedCrossRefGoogle Scholar
  74. 74.
    Oshima, T., Abe, M., Asano, J., et al. (2005). Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2. Blood, 106(9), 3160–3165.PubMedCrossRefGoogle Scholar
  75. 75.
    Ehrlich, L. A., Chung, H. Y., Ghobrial, I., et al. (2005). IL-3 is a potential inhibitor of osteoblast differentiation in multiple myeloma. Blood, 106(4), 1407–1414.PubMedCrossRefGoogle Scholar
  76. 76.
    Giuliani, N., Colla, S., Morandi, F., et al. (2005). Myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation. Blood, 106(7), 2472–2483.PubMedCrossRefGoogle Scholar
  77. 77.
    Hjorth-Hansen, H., Seifert, M. F., Börset, M., Aarset, H., Ostlie, A., Sundan, A., & Waage, A. (1999). Marked osteoblastopenia and reduced bone formation in a model of multiple myeloma bone disease in severe combined immunodeficiency mice. Journal of Bone and Mineral Research, 14(2), 256–263.PubMedCrossRefGoogle Scholar
  78. 78.
    Rokstad, A. M., Holtan, S., Strand, B., Steinkjer, B., Ryan, L., Kulseng, B., & Skjåk-Braek, G. (2002). Microencapsulation of cells producing therapeutic proteins: optimizing cell growth and secretion. TCell Transplant, 11(4), 313–324.Google Scholar
  79. 79.
    Kawasaki, T., Niki, Y., Miyamoto, T., Horiuchi, K., Matsumoto, M., Aizawa, M., & Toyama, Y. (2010). The effect of timing in the administration of hepatocyte growth factor to modulate BMP-2-induced osteoblast differentiation. Biomaterials, 31(6), 1191–1198.PubMedCrossRefGoogle Scholar
  80. 80.
    Standal, T., Abildgaard, N., Fagerli, U. M., Stordal, B., Hjertner, O., Borset, M., & Sundan, A. (2007). HGF inhibits BMP-induced osteoblastogenesis: possible implications for the bone disease of multiple myeloma. Blood, 109(7), 3024–3030.PubMedGoogle Scholar
  81. 81.
    Hideshima, T., Chauhan, D., Podar, K., Schlossman, R. L., Richardson, P., & Anderson, K. C. (2001). Novel therapies targeting the myeloma cell and its bone marrow microenvironment. Seminars in Oncology, 28(6), 607–612.PubMedCrossRefGoogle Scholar
  82. 82.
    Zhao, L., Huang, J., Zhang, H., Wang, Y., Matesic, L. E., Takahata, M., Awad, H., Chen, D., & Xing, L. (2011). Tumor necrosis factor inhibits mesenchymal stem cell differentiation into osteoblasts via the ubiquitin E3 ligase Wwp1. Stem Cells, 29(10), 1601–1610. doi: 10.1002/stem.703.PubMedCrossRefGoogle Scholar
  83. 83.
    Olfa, G., Christophe, C., Philippe, L., Romain, S., Khaled, H., Pierre, H., Odile, B., & Jean-Christophe, D. (2010). RUNX2 regulates the effects of TNFalpha on proliferation and apoptosis in SaOs-2 cells. Bone, 46(4), 901–910.PubMedCrossRefGoogle Scholar
  84. 84.
    Vallet, S., Mukherjee, S., Vaghela, N., Hideshima, T., Fulciniti, M., Pozzi, S., Santo, L., Cirstea, D., Patel, K., Sohani, A. R., Guimaraes, A., Xie, W., Chauhan, D., Schoonmaker, J. A., Attar, E., Churchill, M., Weller, E., Munshi, N., Seehra, J. S., Weissleder, R., Anderson, K. C., Scadden, D. T., & Raje, N. (2010). Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. Proceedings of the National Academy of Sciences of the United States of America, 107(11), 5124–5129.PubMedCrossRefGoogle Scholar
  85. 85.
    Chantry, A. D., Heath, D., Mulivor, A. W., Pearsall, S., Baud'huin, M., Coulton, L., Evans, H., Abdul, N., Werner, E. D., Bouxsein, M. L., Key, M. L., Seehra, J., Arnett, T. R., Vanderkerken, K., & Croucher, P. (2010). Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo. Journal of Bone and Mineral Research, 25(12), 2633–2646. doi: 10.1002/jbmr.142. Erratum in: J Bone Miner Res, 26(2), 439.PubMedCrossRefGoogle Scholar
  86. 86.
    Lotinun, S., Pearsall, R. S., Davies, M. V., Marvell, T. H., Monnell, T. E., Ucran, J., Fajardo, R. J., Kumar, R., Underwood, K. W., Seehra, J., Bouxsein, M. L., & Baron, R. (2010). A soluble activin receptor Type IIA fusion protein (ACE-011) increases bone mass via a dual anabolic-antiresorptive effect in Cynomolgus monkeys. Bone, 46(4), 1082–1088.PubMedCrossRefGoogle Scholar
  87. 87.
    Abdulkadyrov KM, Salogub GN, Khuazheva NK, Woolf R, Haltom E, Borgstein NG, Knight R, Renshaw G, Yang Y, Sherman ML. (2009). ACE-011, a Soluble Activin Receptor Type Iia IgG-Fc Fusion Protein, Increases Hemoglobin (Hb) and Improves Bone Lesions in Multiple Myeloma Patients Receiving Myelosuppressive Chemotherapy: Preliminary Analysis, American Society of Hematology (ASH) Meeting, Abstract 749.Google Scholar
  88. 88.
    Brunetti, G., Oranger, A., Mori, G., Specchia, G., Rinaldi, E., Curci, P., Zallone, A., Rizzi, R., Grano, M., & Colucci, S. (2011). Sclerostin is overexpressed by plasma cells from multiple myeloma patients. Ann NY Acad Sci, 1237, 19–23. doi: 10.1111/j.1749-6632.2011.06196.x.PubMedCrossRefGoogle Scholar
  89. 89.
    Mendoza-Villanueva, D., Zeef, L., & Shore, P. (2011). Metastatic breast cancer cells inhibit osteoblast differentiation through the Runx2/CBFβ-dependent expression of the Wnt antagonist, sclerostin. Breast Cancer Research, 13(5), R106.PubMedCrossRefGoogle Scholar
  90. 90.
    van Lierop, A. H., Hamdy, N. A., Hamersma, H., van Bezooijen, R. L., Power, J., Loveridge, N., & Papapoulos, S. E. (2011). Patients with sclerosteosis and disease carriers: human models of the effect of sclerostin on bone turnover. Journal of Bone and Mineral Research, 26(12), 2804–2811. doi: 10.1002/jbmr.474.PubMedCrossRefGoogle Scholar
  91. 91.
    Paszty, C., Turner, C. H., & Robinson, M. K. (2010). Sclerostin: a gem from the genome leads to bone-building antibodies. Journal of Bone and Mineral Research, 25(9), 1897–1904.PubMedCrossRefGoogle Scholar
  92. 92.
    Terpos, E., Christoulas, D., Katodritou, E., Bratengeier, C., Gkotzamanidou, M., Michalis, E., Delimpasi, S., Pouli, A., Meletis, J., Kastritis, E., Zervas, K., & Dimopoulos, M. A. (2011). Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symptomatic myeloma: reduction post-bortezomib monotherapy. International Journal of Cancer. doi: 10.1002/ijc.27342.
  93. 93.
    D'Souza, S., del Prete, D., Jin, S., Sun, Q., Huston, A. J., Kostov, F. E., Sammut, B., Hong, C. S., Anderson, J. L., Patrene, K. D., Yu, S., Velu, C. S., Xiao, G., Grimes, H. L., Roodman, G. D., & Galson, D. L. (2011). Gfi1 expressed in bone marrow stromal cells is a novel osteoblast suppressor in patients with multiple myeloma bone disease. Blood, 118(26), 6871–6880.PubMedCrossRefGoogle Scholar
  94. 94.
    Guise, T. A., Yin, J. J., & Mohammad, K. S. (2003). Role of endothelin-1 in osteoblastic bone metastases. Cancer, 97(3 Suppl), 779–784.PubMedCrossRefGoogle Scholar
  95. 95.
    Granchi, S., Brocchi, S., Bonaccorsi, L., Baldi, E., Vinci, M. C., Forti, G., Serio, M., & Maggi, M. (2001). Endothelin-1 production by prostate cancer cell lines is up-regulated by factors involved in cancer progression and down-regulated by androgens. Prostate, 49(4), 267–277.PubMedCrossRefGoogle Scholar
  96. 96.
    Clines, G. A., Mohammad, K. S., Bao, Y., et al. (2007). Dickkopf homolog 1 mediates endothelin-1-stimulated new bone formation. Molecular Endocrinology, 21(2), 486–498.PubMedCrossRefGoogle Scholar
  97. 97.
    Yuyama, H., Koakutsu, A., Fujiyasu, N., Tanahashi, M., Fujimori, A., Sato, S., Shibasaki, K., Tanaka, S., Sudoh, K., Sasamata, M., & Miyata, K. (2004). Effects of selective endothelin ET(A) receptor antagonists on endothelin-1-induced potentiation of cancer pain. European Journal of Pharmacology, 492(2–3), 177–182.PubMedCrossRefGoogle Scholar
  98. 98.
    Yi, B., Williams, P. J., Niewolna, M., et al. (2002). Tumor-derived platelet-derived growth factor-BB plays a critical role in osteosclerotic bone metastasis in an animal model of human breast cancer. Cancer Research, 62(3), 917–923.PubMedGoogle Scholar
  99. 99.
    Dai, J., Keller, J., Zhang, J., et al. (2005). Bone morphogenetic protein-6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism. Cancer Research, 65(18), 8274–8285.PubMedCrossRefGoogle Scholar
  100. 100.
    Hall, C. L., Bafico, A., Dai, J., et al. (2005). Prostate cancer cells promote osteoblastic bone metastases through Wnts. Cancer Research, 65(17), 7554–7560.PubMedGoogle Scholar
  101. 101.
    Achbarou, A., Kaiser, S., Tremblay, G., et al. (1994). Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo. Cancer Research, 54(9), 2372–2377.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Hematology OncologyIndiana University School of MedicineIndianapolisUSA

Personalised recommendations