A crosstalk between myeloma cells and marrow stromal cells stimulates production of DKK1 and interleukin-6: a potential role in the development of lytic bone disease and tumor progression in multiple myeloma.
Multiple myeloma (MM) is a malignancy of antibody-secreting plasma cells. B-cell plasmacytomas stimulate bone resorption and angiogenesis, resulting in osteolytic lesions in the skeleton which persist upon successful treatment of the malignancy with chemotherapy. We found that an interaction between MM cells and mesenchymal stem cells (MSCs) from bone marrow stroma results in the formation and persistence of osteolytic bone lesions. It is known that MM cells activate osteoclast activity and secrete high levels of the Wnt inhibitor, Dickkopf-1, which prevents MSCs from differentiating into osteoblasts. We show that the Wnt signaling activator 6-bromoindirubin-3'-monoxime (BIO) releases MSCs from the osteoinhibitory effects of Dickkopf-1, whereas LiCl treatment does not. Additionally, we show that the >5-kDa fraction of MSC-conditioned medium promotes the proliferation of Dickkopf-1-secreting MM cells and that an interleukin-6 (IL-6)-neutralizing antibody blocks this effect. IL-6 expression levels were higher in undifferentiated MSCs than in MSCs treated with osteogenic medium, remained high in the presence of Dkk1, and were reduced by BIO treatment. Therefore, BIO treatment reduces the MSC-stimulated proliferation of MM cells and may enable MSCs to repair existing osteolytic lesions.
Gunn
William G
WG
Center for Gene Therapy, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
Conley
Adam
A
Deininger
Lisa
L
Olson
Scott D
SD
Prockop
Darwin J
DJ
Gregory
Carl A
CA
D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002450:Cell Communication; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008954:Models, Biological; D009101:Multiple Myeloma / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis; D010014:Osteolysis / Q000209:etiology / Q000628:therapy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*; D000093242:Interleukin-6 Inhibitors
D017077:Culture Media, Conditioned; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D012333:RNA, Messenger; D000093242:Interleukin-6 Inhibitors; C501126:DKK1 protein, human