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Blood, 15 July 2008, Vol. 112, No. 2, pp. 216-217. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Edwards, C. M. Search for Related Content PubMed PubMed Citation Articles by Edwards, C. M. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Comment on Qiang et al, page 374 Wnt signaling: bone's defense against myeloma Claire M. Edwards VANDERBILT CENTER FOR BONE BIOLOGY In this issue of Blood, Qiang and colleagues show that increasing Wnt signaling within the myeloma bone microenvironment inhibits myeloma bone disease and consequently reduces tumor burden. For many years, the osteoclast was thought to be the main culprit in the development of the destructive osteolytic bone disease that is a characteristic feature of multiple myeloma. Only more recently were suppression of osteoblastogenesis and bone formation found to contribute to the systemic bone loss and osteolytic bone lesions associated with myeloma bone disease. Current therapies targeting the osteoclast are effective at preventing further bone destruction, but cannot replace bone that has already been lost. Therefore, targeting bone formation in multiple myeloma is an attractive therapeutic approach. Compelling evidence for the critical role Wnt signaling plays in promoting osteoblast differentiation and bone formation, and the discovery of Dickkopf1 as a mediator of the reduction in osteoblastic bone formation in multiple myeloma, both identify the Wnt signaling pathway as a potential therapeutic target in multiple myeloma.1–3 Qiang and colleagues took 2 complementary approaches to exploring this new avenue: overexpression of Wnt3A in myeloma cells, and systemic Wnt3A treatment. Both approaches use the severe combined immunodeficient (SCID) hu myeloma model, in which human myeloma cell growth is restricted to human bone implanted into immunodeficient mice. Under normal circumstances, the SCID-hu myeloma model is associated with tumor growth and osteolysis of the human bone fragment. However, increasing Wnt signaling with Wnt3A resulted in a reduction in tumor burden, an increase in bone mineral density, and a decrease in the osteoclast:osteoblast ratio. These data support an earlier study by Edwards et al in which systemic activation of Wnt signaling with lithium chloride was shown to prevent myeloma bone disease and indirectly reduce tumor burden in bone in the 5TGM1 murine model of myeloma.4 The direct effect of Wnt signaling on myeloma cells remains controversial. Qiang and colleagues demonstrate that although Wnt3A activates Wnt signaling in myeloma cells, this is not associated with an increase in proliferation, either in vitro or in vivo. This eliminates the possibility of direct proliferative effects through Wnt signaling in myeloma cells in this model. Although bone formation is not directly assessed, evidence is provided to support a direct effect of Wnt3A in increasing Wnt signaling in cells of the osteoblast lineage. Taken together, the results presented by Qiang et al suggest that, within the bone microenvironment, Wnt3A acts to promote osteoblast differentiation and suppress osteoclastogenesis. This results in inhibition of myeloma bone disease and consequent indirect suppression of tumor growth. These studies advance our knowledge of myeloma bone disease, and raise questions regarding the balance of agonists and antagonists of the Wnt signaling pathway in myeloma, and the function of Wnt signaling in myeloma cells. View larger version (83K): [in this window] [in a new window]   Effect of Wnt3A in the bone microenvironment in multiple myeloma. (A) Myeloma cells promote the development of the associated bone disease, and the bone disease promotes tumor growth and survival, resulting in a vicious cycle of increased tumor burden and increased osteolytic bone disease. (B) Wnt3A enhances Wnt signaling in the bone marrow microenvironment. This has no direct effect on myeloma-cell growth, but acts to increase bone formation and decrease bone resorption. This inhibits myeloma bone disease and, consequently, indirectly reduces tumor burden in bone. Professional illustration by Alice Chen.   The conclusions by Qiang and colleagues provide strong support for the potential of targeting the Wnt signaling pathway within the bone marrow microenvironment for the treatment of myeloma bone disease. Furthermore, they highlight the complex interdependence between myeloma cells and host cells of the bone marrow niche, along with the importance of studying myeloma within the appropriate microenvironment. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Baron R, Rawadi G. Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology. 2007;148:2635–2643.[Abstract/Free Full Text] Tian E, Zhan F, Walker R, et al. The role of the Wnt-signaling antagonist in the development of osteolytic lesions in multiple myeloma. N Engl J Med. 2003;349:2483–2494.[Abstract/Free Full Text] Yaccoby S, Ling W, Zhan F, Walker R, Barlogie B, Shaughnessy JD Jr. Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood. 2007;109:2106–2111.[Abstract/Free Full Text] Edwards CM, Edwards JR, Lwin ST, et al. Increasing Wnt signaling in the bone marrow microenvironment inhibits the development of myeloma bone disease and reduces tumor burden in bone in vivo. Blood. 2008;111:2833–2842.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Wnt3a signaling within bone inhibits multiple myeloma bone disease and tumor growth Ya-Wei Qiang, John D. Shaughnessy, Jr, and Shmuel Yaccoby Blood 2008 112: 374-382. [Abstract] [Full Text] [PDF] This article has been cited by other articles: J. J. Pinzone, B. M. Hall, N. K. Thudi, M. Vonau, Y.-W. Qiang, T. J. Rosol, and J. D. Shaughnessy Jr The role of Dickkopf-1 in bone development, homeostasis, and disease Blood, January 15, 2009; 113(3): 517 - 525. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Edwards, C. M. Search for Related Content PubMed PubMed Citation Articles by Edwards, C. M. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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