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[Cancer Research 63, 5438-5445, September 1, 2003]
© 2003 American Association for Cancer Research

Regular Articles

Receptor Activator of Nuclear Factor-{kappa}B Ligand Expression by Human Myeloma Cells Mediates Osteoclast Formation in Vitro and Correlates with Bone Destruction in Vivo1

Amanda N. Farrugia2, Gerald J. Atkins2, L. Bik To, Beiqing Pan, Noemi Horvath, Panagiota Kostakis, David M. Findlay, Peter Bardy and Andrew C. W. Zannettino3

Myeloma and Mesenchymal Research Group, Matthew Roberts Foundation Laboratory, Division of Haematology, Institute of Medical and Veterinary Science and The Hanson Institute, Adelaide [A. N. F., B. P., P. K., A. C. W. Z.]; Department of Orthopaedics and Trauma, University of Adelaide, Adelaide [G. J. A., P. K., D. M. F.]; Division of Haematology, The Institute of Medical and Veterinary Science, Adelaide [L. B. T., N. H.]; and Division of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville [P. B.], South Australia

Multiple myeloma (MM) is an incurable B-cell malignancy able to mediate massive destruction of the axial skeleton. The aim of this study was to examine the involvement of the tumor necrosis factor-ligand family member, receptor activator of nuclear factor-{kappa}B ligand (RANKL), and its naturally occurring antagonist, osteoprotegerin (OPG), in MM biology. Using flow cytometry and two independent anti-RANKL antibodies, we demonstrate RANKL expression in CD38+++CD45+ and CD38+++CD45- myeloma plasma cell (MPC) subpopulations derived from patients with osteolytic MM. In addition, highly purified subpopulations of MPC express mRNA for both transmembrane and soluble RANKL isoforms but lack expression of OPG mRNA and protein. We also show that RANKL expressed by MPC is functional as in vitro coculture of CD38+++CD45+ and CD38+++CD45- MPC subpopulations with peripheral blood mononuclear cells resulted in the formation of multinucleate, tartrate-resistant acid phosphatase-positive osteoclasts-like cells capable of forming typical resorption pits. Furthermore, high expression of membrane-associated RANKL by CD38+++ MPC correlated with the presence of multiple radiological bone lesions in individuals with MM. Together, our data strongly suggest that RANKL expression by MPC confers on them the ability to participate directly in the formation of osteoclast in vivo and extends our knowledge of the involvement of RANKL and OPG in the osteolysis characteristic of this disease.




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