Document Detail

Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma.
MedLine Citation:
PMID:  18305214     Owner:  NLM     Status:  MEDLINE    
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.
Ya-Wei Qiang; Yu Chen; Owen Stephens; Nathan Brown; Bangzheng Chen; Joshua Epstein; Bart Barlogie; John D Shaughnessy
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-02-27
Journal Detail:
Title:  Blood     Volume:  112     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2008 Jul 
Date Detail:
Created Date:  2008-06-24     Completed Date:  2008-07-17     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  196-207     Citation Subset:  AIM; IM    
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
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MeSH Terms
Base Sequence
Cell Differentiation
Cell Line
Cell Line, Tumor
Coculture Techniques
DNA Primers / genetics
Gene Expression
Gene Silencing
Intercellular Signaling Peptides and Proteins / genetics,  metabolism*,  pharmacology
Multiple Myeloma / complications*,  genetics,  metabolism*,  pathology
Osteoblasts / metabolism*,  pathology
Osteolysis / etiology*,  genetics,  metabolism*,  pathology
Osteoprotegerin / biosynthesis*,  genetics
RANK Ligand / biosynthesis*
RNA, Messenger / genetics,  metabolism
RNA, Neoplasm / genetics,  metabolism
Recombinant Proteins / pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Tumor Cells, Cultured
Wnt Proteins / metabolism*
Grant Support
Reg. No./Substance:
0/DKK1 protein, human; 0/DNA Primers; 0/Intercellular Signaling Peptides and Proteins; 0/Osteoprotegerin; 0/RANK Ligand; 0/RNA, Messenger; 0/RNA, Neoplasm; 0/Recombinant Proteins; 0/TNFRSF11B protein, human; 0/TNFSF11 protein, human; 0/Wnt Proteins; 0/Wnt-3 protein
Comment In:
Blood. 2008 Jul 1;112(1):3-4   [PMID:  18574032 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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