Characterization of Wnt/beta-catenin signalling in osteoclasts in multiple myeloma.
We recently showed that increasing Wnt/beta-catenin signalling in the bone marrow microenvironment or in multiple myeloma (MM) cells clearly suppresses osteoclastogenesis in SCID-hu mice; however, this regulation of osteoclastogenesis could result directly from activation of Wnt/beta-catenin signalling in osteoclasts or indirectly from effects on osteoblasts. The present studies characterized Wnt/beta-catenin signalling and its potential role in osteoclasts. Systematic analysis of expression of WNT, FZD, LRP and TCF gene families demonstrated that numerous Wnt-signalling components were expressed in human osteoclasts from patients with MM. Functional Wnt/beta-catenin signalling was identified by accumulation of total and active beta-catenin and increases in Dvl-3 protein in response to Wnt3a or LiCl. Furthermore, Wnt-induced increases in beta-catenin and Dvl-3 were attenuated by Wnt antagonists Dkk1 and sFRP1. Finally, Wnt3a-induced TCF/LEF transcriptional activity suggests that canonical Wnt signalling is active in osteoclasts. Supernatants from dominant-negative-beta-catenin-expressing osteoblast clones significantly stimulated tartrate-resistant acid phosphatase-positive osteoclast formation from primary MM-derived osteoclasts, compared with supernatants from control cells. These results suggested that Wnt/beta-catenin signalling is active in osteoclasts in MM and is involved in osteoclastogenesis in bone marrow, where it acts as a negative regulator of osteoclast formation in an osteoblast-dependent manner in MM.
Qiang
Ya-Wei
YW
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, 72205, USA. yqiang@uams.edu <yqiang@uams.edu>
Chen
Yu
Y
Brown
Nathan
N
Hu
Bo
B
Epstein
Joshua
J
Barlogie
Bart
B
Shaughnessy
John D
JD
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D000072261:Dishevelled Proteins; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D017930:Genes, Reporter / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C000606584:DVL3 protein, human; D000072261:Dishevelled Proteins; C000606585:Dvl3 protein, mouse; C489740:FZD1 protein, human; D051157:Frizzled Receptors; D036341:Intercellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D051153:Wnt Proteins; D051176:beta Catenin; D008156:Luciferases