32. Oshima T, Abe M, Asano J, Hara T, Kitazoe K, et al. (2005) Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2. Blood 106: 3160–3165. 33. Taube T, Elomaa I, Blomqvist C, Beneton MNC, Kanis JA (1994) Histomorphometric Evidence for Osteoclast-Mediated Bone-Resorption in Metastatic Breast-Cancer. Bone 15: 161–166. 34. Vukmirovic-Popovic S, Colterjohn N, Lhotak S, Duivenvoorden WCM, Orr FW, et al. (2002) Morphological, histomorphometric, and microstructural alterations in human bone metastasis from breast carcinoma. Bone 31: 529–535. 35. Kulenkampff HA, Dreyer T, Kersjes W, Delling G (1986) Histomorphometric Analysis of Osteoclastic Bone-Resorption in Metastatic Bone-Disease from Various Primary Malignomas. Virchows Archiv a-Pathological Anatomy and Histopathology 409: 817–828. 36. Parfitt A (1995) Bone remodeling, normal and abnormal: a biological basis for the understanding of cancer-related bone disease and its treatment. The Canadian journal of oncology 5: 1–10. 37. Mastro AM, Gay CV, Welch DR, Donahue HJ, Jewell J, et al. (2004) Breast cancer cells induce osteoblast apoptosis: A possible contributor to bone degradation. Journal of Cellular Biochemistry 91: 265–276. 38. Mercer RR, Miyasaka C, Mastro AM (2004) Metastatic breast cancer cells suppress osteoblast adhesion and differentiation. Clinical & Experimental Metastasis 21: 427–435. 39. Morrissey C, Lai JS, Brown LG, Wang YC, Roudier MP, et al. (2010) The expression of osteoclastogenesis-associated factors and osteoblast response to osteolytic prostate cancer cells. Prostate 70: 412–424. 40. Brunet LJ, McMahon JA, McMahon AP, Harland RM (1998) Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 280: 1455–1457. 41. Devlin RD, Du Z, Pereira RC, Kimble RB, Economides AN, et al. (2003) Skeletal overexpression of noggin results in osteopenia and reduced bone formation. Endocrinology 144: 1972–1978. 42. Wu XB, Li Y, Schneider A, Yu W, Rajendren G, et al. (2003) Impaired osteoblastic differentiation, reduced bone formation, and severe osteoporosis in noggin-overexpressing mice. J Clin Invest 112: 924–934. 43. Barnes J, Anthony CT, Wall N, Steiner MS (1995) Bone morphogenetic protein- 6 expression in normal and malignant prostate. World J Urol 13: 337–343. 44. Hamdy FC, Autzen P, Robinson MC, Horne CH, Neal DE, et al. (1997) Immunolocalization and messenger RNA expression of bone morphogenetic protein-6 in human benign and malignant prostatic tissue. Cancer Res 57: 4427–4431. 45. Dai J, Keller J, Zhang J, Lu Y, Yao Z, et al. (2005) Bone morphogenetic protein- 6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism. Cancer Res 65: 8274–8285. 46. Hall CL, Kang S, MacDougald OA, Keller ET (2006) Role of Wnts in prostate cancer bone metastases. J Cell Biochem 97: 661–672. 47. Harris SE, Harris MA, Mahy P, Wozney J, Feng JQ, et al. (1994) Expression of bone morphogenetic protein messenger RNAs by normal rat and human prostate and prostate cancer cells. Prostate 24: 204–211. 48. Buijs JT, Henriquez NV, van Overveld PG, van der Horst G, ten Dijke P, et al. (2007) TGF-beta and BMP7 interactions in tumour progression and bone metastasis. Clin Exp Metastasis 24: 609–617. 49. Buijs JT, Rentsch CA, van der Horst G, van Overveld PG, Wetterwald A, et al. (2007) BMP7, a putative regulator of epithelial homeostasis in the human prostate, is a potent inhibitor of prostate cancer bone metastasis in vivo. Am J Pathol 171: 1047–1057. Role of Noggin in Osteolytic Bone Metastasis 50. Neri B, Cecchettin M, Pacini P, Bartalucci S, Gemelli MT, et al. (1989) Osteocalcin as a biological marker in the therapeutic management of breast cancer bone metastases. Cancer Invest 7: 551–555. 51. Yaccoby S, Ling W, Zhan F, Walker R, Barlogie B, et al. (2007) Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood 109: 2106–2111. 52. Heath DJ, Chantry AD, Buckle CH, Coulton L, Shaughnessy JD, Jr., et al. (2009) Inhibiting Dickkopf-1 (Dkk1) removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma. J Bone Miner Res 24: 425–436. 53. Bu G, Lu W, Liu CC, Selander K, Yoneda T, et al. (2008) Breast cancer-derived Dickkopf1 inhibits osteoblast differentiation and osteoprotegerin expression: implication for breast cancer osteolytic bone metastases. Int J Cancer 123: 1034–1042. 54. Hall CL, Bafico A, Dai J, Aaronson SA, Keller ET (2005) Prostate cancer cells promote osteoblastic bone metastases through Wnts. Cancer Res 65: 7554–7560. 55. Voorzanger-Rousselot N, Goehrig D, Journe F, Doriath V, Body JJ, et al. (2007) Increased Dickkopf-1 expression in breast cancer bone metastases. Br J Cancer 97: 964–970. 56. Hartmann C (2006) A Wnt canon orchestrating osteoblastogenesis. Trends in Cell Biology 16: 151–158. 57. Dai JL, Hall CL, Escara-Wilke J, Mizokami A, Keller JM, et al. (2008) Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent and independent mechanisms. Cancer Research 68: 5785–5794. 58. Ohazama A, Johnson EB, Ota MS, Choi HY, Porntaveetus T, et al. (2008) Lrp4 modulates extracellular integration of cell signaling pathways in development. PLoS One 3: e4092. 59. Lintern KB, Guidato S, Rowe A, Saldanha JW, Itasaki N (2009) Character- ization of Wise Protein and Its Molecular Mechanism to Interact with both Wnt and BMP Signals. Journal of Biological Chemistry 284: 23159–23168. 60. Chanda D, Isayeva T, Kumar S, Hensel JA, Sawant A, et al. (2009) Therapeutic Potential of Adult Bone Marrow-Derived Mesenchymal Stem Cells in Prostate Cancer Bone Metastasis. Clinical Cancer Research 15: 7175–7185. 61. van der Pluijm G, Que I, Sijmons B, Buijs JT, Lowik CWGM, et al. (2005) Interference with the microenvironmental support impairs the de novo formation of bone metastases in vivo. Cancer Research 65: 7682–7690. 62. Sasaki A, Boyce BF, Story B, Wright KR, Chapman M, et al. (1995) Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice. Cancer Res 55: 3551–3557. 63. Yaccoby S, Wezernan MJ, Zangari M, Walker R, Cottler-Fox M, et al. (2006) Inhibitory effects of osteoblasts and increased bone formation on myeloma in novel culture systems and a myelomatous mouse model. Haematologica-the Hematology Journal 91: 192–199. 64. Feeley BT, Krenek L, Liu N, Hsu WK, Gamradt SC, et al. (2006) Overexpression of noggin inhibits BMP-mediated growth of osteolytic prostate cancer lesions. Bone 38: 154–166. 65. Dougall WC, Chaisson M (2006) The RANK/RANKL/OPG triad in cancer- induced bone diseases. Cancer and Metastasis Reviews 25: 541–549. 66. Buckle CH, Neville-Webbe HL, Croucher PI, Lawson MA (2010) Targeting RANK/RANKL in the Treatment of Solid Tumours and Myeloma. Curr Pharm Des. PLoS ONE | www.plosone.org 10 January 2011 | Volume 6 | Issue 1 | e16078