SEARCH:   Advanced

Blood, 1 July 2008, Vol. 112, No. 1, pp. 196-207. Prepublished online as a Blood First Edition Paper on February 27, 2008; DOI 10.1182/blood-2008-01-132134. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-01-132134v1 112/1/196    most recent 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 Google Scholar Articles by Qiang, Y.-W. Articles by Shaughnessy, J. D. PubMed PubMed Citation Articles by Qiang, Y.-W. Articles by Shaughnessy, J. D., Jr Related Collections Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma Ya-Wei Qiang1, Yu Chen1, Owen Stephens1, Nathan Brown1, Bangzheng Chen1, Joshua Epstein1, Bart Barlogie1, and John D. Shaughnessy, Jr1 1 Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock Multiple myeloma (MM) is characterized by osteolytic bone lesions (OBL) that arise as a consequence of osteoblast inactivation and osteoclast activation adjacent to tumor foci within bone. Wnt signaling in osteoblasts regulates osteoclastogenesis through the differential activation and inactivation of Receptor Activator of Nuclear factor Kappa B Ligand (RANKL) and osteoprotegerin (OPG), positive and negative regulators of osteoclast differentiation, respectively. We demonstrate here that MM cell–derived DKK1, a soluble inhibitor of canonical Wnt signaling, disrupted Wnt3a-regulated OPG and RANKL expression in osteoblasts. Confirmed in multiple independent assays, we show that pretreatment with rDKK1 completely abolished Wnt3a-induced OPG mRNA and protein production by mouse and human osteoblasts. In addition, we show that Wnt3a-induced OPG expression was diminished in osteoblasts cocultured with a DKK1-expressing MM cell line or primary MM cells. Finally, we show that bone marrow sera from 21 MM patients significantly suppressed Wnt3a-induced OPG expression and enhanced RANKL expression in osteoblasts in a DKK1-dependent manner. These results suggest that DKK1 may play a key role in the development of MM-associated OBL by directly interrupting Wnt-regulated differentiation of osteoblasts and indirectly increasing osteoclastogenesis via a DKK1-mediated increase in RANKL-to-OPG ratios. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: MM-induced osteolysis: partners in crime Carl Gregory Blood 2008 112: 3-4. [Full Text] [PDF] This article has been cited by other articles: Y.-W. Qiang, J. D. Shaughnessy Jr, and S. Yaccoby Wnt3a signaling within bone inhibits multiple myeloma bone disease and tumor growth Blood, July 15, 2008; 112(2): 374 - 382. [Abstract] [Full Text] [PDF] X. Li, A. Pennisi, and S. Yaccoby Role of decorin in the antimyeloma effects of osteoblasts Blood, July 1, 2008; 112(1): 159 - 168. [Abstract] [Full Text] [PDF]

	Copyright © 2008 by American Society of Hematology         Online ISSN: 1528-0020