Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma.
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.
Qiang
Ya-Wei
YW
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Chen
Yu
Y
Stephens
Owen
O
Brown
Nathan
N
Chen
Bangzheng
B
Epstein
Joshua
J
Barlogie
Bart
B
Shaughnessy
John D
JD
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D009101:Multiple Myeloma / Q000150:complications* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010014:Osteolysis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053244:Osteoprotegerin / Q000096:biosynthesis* / Q000235:genetics; D053245:RANK Ligand / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein
C501126:DKK1 protein, human; D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011994:Recombinant Proteins; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse