Inhibiting Dickkopf-1 (Dkk1) Removes Suppression of Bone Formation and Prevents the Development of Osteolytic Bone Disease in Multiple Myeloma

Authors

  • Deborah J Heath,

    1. Academic Unit of Bone Biology, Section of Musculoskeletal Sciences, University of Sheffield School of Medicine and Biomedical Sciences, Sheffield, Yorkshire, United Kingdom
    2. These authors contributed equally to this work
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  • Andrew D Chantry,

    1. Academic Unit of Bone Biology, Section of Musculoskeletal Sciences, University of Sheffield School of Medicine and Biomedical Sciences, Sheffield, Yorkshire, United Kingdom
    2. These authors contributed equally to this work
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  • Clive H Buckle,

    1. Academic Unit of Bone Biology, Section of Musculoskeletal Sciences, University of Sheffield School of Medicine and Biomedical Sciences, Sheffield, Yorkshire, United Kingdom
    2. These authors contributed equally to this work
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  • Les Coulton,

    1. Academic Unit of Bone Biology, Section of Musculoskeletal Sciences, University of Sheffield School of Medicine and Biomedical Sciences, Sheffield, Yorkshire, United Kingdom
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  • John D Shaughnessy Jr,

    1. Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
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  • Holly R Evans,

    1. Academic Unit of Bone Biology, Section of Musculoskeletal Sciences, University of Sheffield School of Medicine and Biomedical Sciences, Sheffield, Yorkshire, United Kingdom
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  • John A Snowden,

    1. Department of Haematology, Royal Hallamshire Hospital, Sheffield, Yorkshire, United Kingdom
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  • David R Stover,

    1. Novartis Institutes for Biomedical Research Incorporated, Cambridge, Massachusetts, USA
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  • Karin Vanderkerken,

    1. Department of Haematology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium
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  • Peter I Croucher Jr

    Corresponding author
    1. Academic Unit of Bone Biology, Section of Musculoskeletal Sciences, University of Sheffield School of Medicine and Biomedical Sciences, Sheffield, Yorkshire, United Kingdom
    • Address reprint requests to: Peter I Croucher, PhD, Academic Unit of Bone Biology, Section of Musculoskeletal Science, University of Sheffield School of Medicine, and Biomedical Sciences, Beech Hill Road, Sheffield, Yorkshire S10 2RX, UK
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Errata

This article is corrected by:

  1. Errata: Erratum: Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo Volume 27, Issue 9, 2038, Article first published online: 17 August 2012

  • Dr Stover is an employee, has corporate appointments, and has stock ownership of Novartis. Dr Shaughnessy has equity interests, grants, and licensing arrangements with Novartis. All other authors state that they have no conflicts of interest.

Abstract

Multiple myeloma (MM) is associated with the development of osteolytic bone disease, mediated by increased osteoclastic bone resorption and impaired osteoblastic bone formation. Dickkopf-1 (Dkk1), a soluble inhibitor of wingless/int (Wnt) signaling and osteoblastogenesis, is elevated in patients with MM and correlates with osteolytic bone disease. In this study, we investigated the effect of inhibiting Dkk1 on the development of osteolytic lesions in the 5T2MM murine model of myeloma. We showed that Dkk1 is expressed by murine 5T2MM myeloma cells. Injection of 5T2MM cells into C57BL/KaLwRij mice resulted in the development of osteolytic bone lesions (p < 0.05), mediated by increased osteoclast numbers (p < 0.001) and a decrease in osteoblast numbers (p < 0.001) and mineralizing surface (p < 0.05). Mice bearing 5T2MM cells were treated with an anti-Dkk1 antibody (BHQ880, 10 mg/kg, IV, twice weekly for 4 wk) from time of paraprotein detection. Anti-Dkk1 treatment prevented 5T2MM-induced suppression of osteoblast numbers (p < 0.001) and surface (p < 0.001). Treatment increased mineralizing surface by 28% and bone formation rate by 25%; however, there was no change in mineral apposition rate. Inhibiting Dkk1 had no effect on osteoclast numbers. μCT analysis showed that anti-Dkk1 treatment significantly protected against 5T2MM-induced trabecular bone loss (p < 0.05) and reduced the development of osteolytic bone lesions (p < 0.05). Treatment had no significant effect on tumor burden. These data suggest that inhibiting Dkk1 prevents the suppression of bone formation and in doing so is effective in preventing the development of osteolytic bone disease in myeloma, offering an effective therapeutic approach to treating this clinically important aspect of myeloma.

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