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Myeloma

Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma

Leukemia volume 22, pages 1925–1932 (2008)Cite this article

An Erratum to this article was published on 15 October 2008

Abstract

Osteolytic bone disease in multiple myeloma (MM) is caused by enhanced osteoclast (OCL) activation and inhibition of osteoblast function. Lenalidomide and bortezomib have shown promising response rates in relapsed and newly diagnosed MM, and bortezomib has recently been reported to inhibit OCLs. We here investigated the effect of lenalidomide on OCL formation and osteoclastogenesis in comparison with bortezomib. Both drugs decreased αVβ3-integrin, tartrate-resistant acid phosphatase-positive cells and bone resorption on dentin disks. In addition, both agents decreased receptor activator of nuclear factor-κB ligand (RANKL) secretion of bone marrow stromal cells (BMSCs) derived from MM patients. We identified PU.1 and pERK as major targets of lenalidomide, and nuclear factor of activated T cells of bortezomib, resulting in inhibition of osteoclastogenesis. Furthermore, downregulation of cathepsin K, essential for resorption of the bone collagen matrix, was observed. We demonstrated a significant decrease of growth and survival factors including macrophage inflammatory protein-α, B-cell activating factor and a proliferation-inducing ligand. Importantly, in serum from MM patients treated with lenalidomide, the essential bone-remodeling factor RANKL, as well as the RANKL/OPG ratio, were significantly reduced, whereas osteoprotegerin (OPG) was increased. We conclude that both agents specifically target key factors in osteoclastogenesis, and could directly affect the MM-OCL-BMSCs activation loop in osteolytic bone disease.

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Acknowledgements

We thank the patients, nursing staff as well as the clinical research coordinators of the Jerome Lipper Multiple Myeloma Center/Dana-Farber Cancer Institute, for their help in providing serum specimens for this study. This work was supported by the Multiple Myeloma Research Foundation, LeBow Fund to Cure Myeloma (KCA); National Foundation of Cancer Research and NIH grants CA50947, CA78373 and CA10070.

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  1. Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    I Breitkreutz, M S Raab, S Vallet, T Hideshima, N Raje, C Mitsiades, D Chauhan, Y Okawa, N C Munshi, P G Richardson & K C Anderson

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Correspondence to K C Anderson.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Breitkreutz, I., Raab, M., Vallet, S. et al. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. Leukemia 22, 1925–1932 (2008). https://doi.org/10.1038/leu.2008.174

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