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Myeloma

Myeloma cells inhibit non-canonical wnt co-receptor ror2 expression in human bone marrow osteoprogenitor cells: effect of wnt5a/ror2 pathway activation on the osteogenic differentiation impairment induced by myeloma cells

Leukemia volume 27, pages 451–463 (2013)Cite this article

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Abstract

Multiple myeloma (MM) is characterized by the impaired osteogenic differentiation of human mesenchymal stromal cells (hMSCs). Canonical Wnt signaling is critical for the regulation of bone formation, however, recent evidence suggests that the non-canonical Wnt agonist Wnt5a stimulates human osteoblastogenesis through its co-receptor Ror2. The effects of MM cells on non-canonical Wnt signaling and the effect of the activation of this pathway on MM-induced osteoblast exhaustion are not known and were investigated in this study. We found that the osteogenic differentiation of bone marrow hMSCs toward osteoprogenitor cells (PreOB) significantly increased Ror2 expression, and that MM cells inhibit Ror2 expression by PreOB in co-culture by inhibiting the non-canonical Wnt5a signaling. The activation of the non-canonical Wnt pathway in hMSCs by means of Wnt5a treatment and the overexpression of Wnt5 or Ror2 by lentiviral vectors increased the osteogenic differentiation of hMSCs and blunted the inhibitory effect of MM in co-culture. Consistently, Wnt5a inhibition by specific small interfering RNA reduced the hMSC expression of osteogenic markers. Our findings demonstrate that the Wnt5a/Ror2 pathway is involved in the pathophysiology of MM-induced bone disease and that the activation of the non-canonical Wnt5a/Ror2 pathway in hMSCs increases osteogenic differentiation and may counterbalance the inhibitory effect of MM cells.

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Acknowledgements

This study was supported by grants from the International Myeloma Foundation, the Italian Ministry of Health (Progetti Regione Emilia Romagna), and the Associazione Italiana per la Ricerca sul Cancro (AIRC: NG: IG2099 no. 8530; AN: IG4569 and Special Program Molecular Clinical Oncology 5 per mille no. 9965). We would like to thank Rebecca Silbermann for editing the manuscript.

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Authors and Affiliations

  1. Hematology and BMT Center, University of Parma, Parma, Italy

    M Bolzoni, P Storti, D Guasco, D Toscani, S Bonomini, B Dalla Palma, F Russo, F Aversa & N Giuliani

  2. Department of Animal Health, Infectious Diseases Section, University of Parma, Parma, Italy

    G Donofrio & A Capocefalo

  3. Department of Genetics, Micro-organism Biology, Anthropology and Evolution, University of Parma, Parma, Italy

    M Lazzaretti

  4. Department of Clinical Sciences and Community Health, University of Milan, and Hematology 1, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

    L Agnelli & A Neri

  5. Department of heart, University of Parma, Parma, Italy

    F Nicolini

  6. Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, Istituto Ortopedico Rizzoli, Bologna, Italy

    G Lisignoli

  7. MD Anderson Cancer Center, Houston, TX, USA

    S Colla

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  1. M Bolzoni
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Correspondence to N Giuliani.

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Bolzoni, M., Donofrio, G., Storti, P. et al. Myeloma cells inhibit non-canonical wnt co-receptor ror2 expression in human bone marrow osteoprogenitor cells: effect of wnt5a/ror2 pathway activation on the osteogenic differentiation impairment induced by myeloma cells. Leukemia 27, 451–463 (2013). https://doi.org/10.1038/leu.2012.190

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