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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.
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Submitted January 9, 2008
Accepted February 13, 2008
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*
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR
* Corresponding author; email: shaughnessyjohn{at}uams.edu.
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 for the first time 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 in mouse and human osteoblasts. Additionally, we show that Wnt3a-induced OPG expression is diminished in osteoblasts co-cultured 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 DKK-1 mediated increase in RANKL-to-OPG ratios.
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