Journal
BRITISH JOURNAL OF HAEMATOLOGY
Volume 148, Issue 5, Pages 726-738Publisher
WILEY-BLACKWELL PUBLISHING, INC
DOI: 10.1111/j.1365-2141.2009.08009.x
Keywords
Wnt3a; beta-catenin; osteoclast; bone disease; multiple myeloma
Categories
Funding
- Multiple Myeloma Research Foundation
- National Cancer Institute, NIH [CA97513, CA113992]
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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.
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