SEARCH:   Advanced

Blood, 1 July 2008, Vol. 112, No. 1, pp. 3-4. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 CrossRef Google Scholar Articles by Gregory, C. PubMed PubMed Citation Articles by Gregory, C. 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 196 MM-induced osteolysis: partners in crime Carl Gregory TULANE UNIVERSITY HEALTH SCIENCES CENTER In this issue of Blood, Qiang and colleagues explore in detail the role of Wnt inhibition in the progression of multiple myeloma–induced OBLs. Shaughnessy and colleagues were the first to describe a potential role for the canonical Wnt inhibitor, dickkopf-1 (DKK1), 5 years ago when they reported abnormally high levels of the secreted glycoprotein in the blood of individuals newly diagnosed with multiple myeloma (MM).1 Of note was a correlation between the levels of DKK1 and the extent of osteolytic bone lesion (OBL) formation, a hallmark characteristic of the disease. In about 80% of MM patients, OBLs occur throughout the skeleton, causing intractable bone pain and pathological fractures. The MM cells flourish and divide within the cytokine-enriched cavities of the OBLs, perpetuating a destructive cycle that is the major cause of morbidity. Historically, the treatment of OBLs has focused on inhibition of osteoclastogenesis, but even when osteoclast activity is controlled, the lesions never repair, suggesting that MM cells also disrupt osteoblastogenesis. There is evidence that DKK1 affects OBL pathogenesis through inhibition of Wnt-mediated differentiation of osteoprogenitors in the bone marrow, and one would predict that this could lead to attenuation of the repair of bone tissue.1,2 Indeed, Yaccoby, Shaughnessy, and colleagues have demonstrated that administration of DKK1-sequestering antibodies can prevent inhibition of osteogenesis in a model of MM and can reduce the formation of OBLs.3,4 In the current study, Qiang and colleagues have expanded our knowledge of the mechanism of DKK1 action by demonstrating that, in addition to inhibition of osteoblastogenesis, DKK1 causes a drop in osteoprotegerin (OPG) expression and an increase in receptor activator of nuclear factor B ligand (RANKL) output by preexisting osteoblasts. This observation is significant because OPG is the scavenger receptor for the osteoclastogenic protein, RANKL; high ratios of locally secreted RANKL-to-OPG levels result in up-regulated osteoclast activity and bone destruction. Therefore, MM-derived DKK1, in addition to its ability to inhibit osteoblast differentiation, is osteoclastogenic through disruption of RANKL/OPG homeostasis. In a series of in vitro assays, the investigators demonstrate that addition of recombinant Wnt3a to various cultured osteoblast cell lines resulted in up-regulation of OPG output and reduction of RANKL expression. Addition of recombinant DKK1 attenuated the effect by reducing OPG output. This observation was confirmed by DKK1 overexpression and RNAi-mediated silencing in the osteoblast lines. Significantly, DKK1 present in MM cell–conditioned media had similar effects in increasing the ratio of RANKL-to-OPG expression in osteoblasts, but when immunosequestered from the media, there was recovery of OPG expression and a concomitant reduction in the ratio of RANKL-to-OPG output. In support of these findings, Gunn et al2 reported a similar up-regulation of OPG when Wnt signaling in primary human osteoprogenitor cells was up-regulated by treatment with a glycogen-synthetase-3β-inhibitor. If the cell lines used in the study faithfully recapitulate osteoblast physiology, these observations predict a future strategy for the treatment of MM OBLs through coadministration of DKK1-blocking antibodies and OPG. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Tian E, Zhan F, Walker R, et al. The role of Wnt signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med. 2003;349:2483–2494.[Abstract/Free Full Text] Gunn WG, Conley A, Deininger L, Olson SD, Prockop DJ, Gregory CA. A crosstalk between myeloma cells and marrow stromal cells stimulates production of DKK1 and IL-6: a potential role in the development of lytic bone disease and tumor progression in multiple myeloma. Stem Cells. 2005;24:986–991.[CrossRef][Medline] [Order article via Infotrieve] 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] Gregory CA. Advances in multiple myeloma therapy: breaking the cycle. Blood. 2007;109:1798.[Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: 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 Qiang, Yu Chen, Owen Stephens, Nathan Brown, Bangzheng Chen, Joshua Epstein, Bart Barlogie, and John D. Shaughnessy, Jr Blood 2008 112: 196-207. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 CrossRef Google Scholar Articles by Gregory, C. PubMed PubMed Citation Articles by Gregory, C. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

	Blood Online is supported in part by Genentech BioOncology and Biogen Idec
	Copyright © 2008 by American Society of Hematology         Online ISSN: 1528-0020