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First published online 7 March 2006
doi: 10.1242/jcs.02883
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Research Article |
B ligand and inhibits osteoclastogenesis in vitro
1 Biomedical Tissue Research, Department of Biology, University of York, PO Box 373, York, YO10 5YW, UK
2 Department of Anatomy and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK
* Author for correspondence (e-mail: gjs6{at}york.ac.uk)
Accepted 22 November 2005
Reports implicating Wnt signalling in the regulation of bone mass have prompted widespread interest in the use of Wnt mimetics for the treatment of skeletal disorders. To date much of this work has focused on their anabolic effects acting on cells of the osteoblast lineage. In this study we provide evidence that Wnts also regulate osteoclast formation and bone resorption, through a mechanism involving transcriptional repression of the gene encoding the osteoclastogenic cytokine receptor activator of NF
B ligand (RANKL or TNFSF11) expressed by osteoblasts. In co-cultures of mouse mononuclear spleen cells and osteoblasts, inhibition of GSK3ß with LiCl or exposure to Wnt3a inhibited the formation of tartrate-resistant acid phosphatase-positive multinucleated cells compared with controls. However, these treatments had no consistent effect on the differentiation, survival or activity of osteoclasts generated in the absence of supporting stromal cells. Activation of Wnt signalling downregulated RANKL mRNA and protein expression, and overexpression of fulllength ß-catenin, but not transcriptionally inactive ß-catenin 
C(695-781), inhibited RANKL promoter activity. Since previous studies have demonstrated an absence of resorptive phenotype in mice lacking LRP5, we determined expression of a second Wnt co-receptor LRP6 in human osteoblasts, CD14+ osteoclast progenitors and mature osteoclasts. LRP5 expression was undetectable in CD14-enriched cells and mature human osteoclasts, although LRP6 was expressed at high levels by these cells. Our evidence of Wnt-dependent regulation of osteoclastogenesis adds to the growing complexity of Wnt signalling mechanisms that are now known to influence skeletal function and highlights the requirement to develop novel therapeutics that differentially target anabolic and catabolic Wnt effects in bone.
Key words: ß-catenin, Osteoblast, Osteoclast, Receptor activator of NFB ligand, T-cell factor, Wnt
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