| Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma. | |
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MedLine Citation:
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PMID: 18305214 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Ya-Wei Qiang; Yu Chen; Owen Stephens; Nathan Brown; Bangzheng Chen; Joshua Epstein; Bart Barlogie; John D Shaughnessy |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2008-02-27 |
Journal Detail:
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Title: Blood Volume: 112 ISSN: 1528-0020 ISO Abbreviation: Blood Publication Date: 2008 Jul |
Date Detail:
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Created Date: 2008-06-24 Completed Date: 2008-07-17 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 196-207 Citation Subset: AIM; IM |
Affiliation:
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Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Base Sequence Cell Differentiation Cell Line Cell Line, Tumor Coculture Techniques DNA Primers / genetics Gene Expression Gene Silencing Humans Intercellular Signaling Peptides and Proteins / genetics, metabolism*, pharmacology Mice 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 Transfection Tumor Cells, Cultured Wnt Proteins / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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CA113992/CA/NCI NIH HHS; CA97513/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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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 |
| Comments/Corrections | |
Comment In:
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Blood. 2008 Jul 1;112(1):3-4
[PMID:
18574032
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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