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Blood, 30 April 2009, Vol. 113, No. 18, pp. 4319-4330. Prepublished online as a Blood First Edition Paper on February 4, 2009; DOI 10.1182/blood-2008-08-174300. This Article Full Text (PDF) All Versions of this Article: blood-2008-08-174300v1 113/18/4319    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Qiang, Y.-W. Articles by Shaughnessy, J. D. Search for Related Content PubMed PubMed Citation Articles by Qiang, Y.-W. Articles by Shaughnessy, J. D., Jr Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 18, 2008 Accepted January 14, 2009 Bortezomib induces osteoblast differentiation via Wnt-independent activation of -catenin/TCF signaling Ya-Wei Qiang, Bo Hu, Yu Chen, Ying Zhong, Bingyin Shi, Bart Barlogie, and John D. Shaughnessy Jr* Donna D. and Donald M. Laboratory of Myeloma Genetics, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, United States Department of Endocrinology, Xian JiaoTong University School of Medicine, Xian, China * Corresponding author; email: shaughnessyjohn{at}uams.edu. Inhibition of Wnt/-catenin/TCF signaling induces proliferation of mesenchymal stem cells (MSC) and/or suppresses their differentiation into osteoblasts (OB). Osteolysis in multiple myeloma (MM) is related to the suppression of canonical Wnt signaling caused by DKK1, a soluble inhibitor of this pathway secreted by MM cells. Bortezomib (Bzb) can induce OB differentiation in-vitro and in-vivo and its anti-MM efficacy linked to bone anabolic effects. However, the molecular basis of Bzb's action on bone is not completely understood. In the present study we show that Bzb promotes matrix mineralization and calcium deposition by osteoprogenitor cells and primary MSC via Wnt-independent activation of -catenin/TCF signaling. Using affinity pull-down assays with immunoblotting and immunofluorescence we found that Bzb induced stabilization of -catenin. Nuclear translocation of stabilized -catenin was associated with -catenin/TCF transcriptional activity that was independent of the effects of Wnt ligand-receptor-induced signaling or GSK3 activation. Blocking the activation of -catenin/TCF signaling by dominant negative TFC attenuated Bzb-induced matrix mineralization. These results provide evidence that Bzb induces OB differentiation via Wnt-independent activation of -catenin/TCF pathway and suggest that proteasome inhibition therapy in MM may function in part by subverting tumor-induced suppression of canonical Wnt signaling in the bone microenvironment. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. B. Bartel, J. Haessler, T. L. Y. Brown, J. D. Shaughnessy Jr, F. van Rhee, E. Anaissie, T. Alpe, E. Angtuaco, R. Walker, J. Epstein, et al. F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma Blood, September 3, 2009; 114(10): 2068 - 2076. [Abstract] [Full Text] [PDF]

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