Glycosphingolipid synthesis inhibition limits osteoclast activation and myeloma bone disease
Adel Ersek, … , Nicole J. Horwood, Anastasios Karadimitris
Adel Ersek, … , Nicole J. Horwood, Anastasios Karadimitris
Published April 27, 2015
Citation Information: J Clin Invest. 2015;125(6):2279-2292. https://doi.org/10.1172/JCI59987.
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Research Article Oncology

Glycosphingolipid synthesis inhibition limits osteoclast activation and myeloma bone disease

Abstract

Glycosphingolipids (GSLs) are essential constituents of cell membranes and lipid rafts and can modulate signal transduction events. The contribution of GSLs in osteoclast (OC) activation and osteolytic bone diseases in malignancies such as the plasma cell dyscrasia multiple myeloma (MM) is not known. Here, we tested the hypothesis that pathological activation of OCs in MM requires de novo GSL synthesis and is further enhanced by myeloma cell–derived GSLs. Glucosylceramide synthase (GCS) inhibitors, including the clinically approved agent N-butyl-deoxynojirimycin (NB-DNJ), prevented OC development and activation by disrupting RANKL-induced localization of TRAF6 and c-SRC into lipid rafts and preventing nuclear accumulation of transcriptional activator NFATc1. GM3 was the prevailing GSL produced by patient-derived myeloma cells and MM cell lines, and exogenous addition of GM3 synergistically enhanced the ability of the pro-osteoclastogenic factors RANKL and insulin-like growth factor 1 (IGF-1) to induce osteoclastogenesis in precursors. In WT mice, administration of GM3 increased OC numbers and activity, an effect that was reversed by treatment with NB-DNJ. In a murine MM model, treatment with NB-DNJ markedly improved osteolytic bone disease symptoms. Together, these data demonstrate that both tumor-derived and de novo synthesized GSLs influence osteoclastogenesis and suggest that NB-DNJ may reduce pathological OC activation and bone destruction associated with MM.

Authors

Adel Ersek, Ke Xu, Aristotelis Antonopoulos, Terry D. Butters, Ana Espirito Santo, Youridies Vattakuzhi, Lynn M. Williams, Katerina Goudevenou, Lynett Danks, Andrew Freidin, Emmanouil Spanoudakis, Simon Parry, Maria Papaioannou, Evdoxia Hatjiharissi, Aristeidis Chaidos, Dominic S. Alonzi, Gabriele Twigg, Ming Hu, Raymond A. Dwek, Stuart M. Haslam, Irene Roberts, Anne Dell, Amin Rahemtulla, Nicole J. Horwood, Anastasios Karadimitris

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Figure 5

GM3 cooperates with RANKL and IGF-I to promote osteoclastogenesis.

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GM3 cooperates with RANKL and IGF-I to promote osteoclastogenesis. (A) M...
(A) Mouse BM cells were cultured in the presence of 25 ng/ml M-CSF and only 5 ng/ml RANKL (control) and GM3 (0.05, 0.5, or 5 μM), (B) with IGF-1 (25, 50, or 100 ng/ml), or (C) with IGF-1+ GM3 in the presence of RANKL and M-CSF in 96-well plates for 7 days, and OC numbers were evaluated by TRAP staining. A representative experiment of 3, each performed in triplicate assays, is shown (n = 3). Error bars correspond to SEM. Statistical analysis was performed using one-way ANOVA followed by Tukey’s multiple comparisons test (*P < 0.05, **P < 0.01, ***P < 0.001 versus control).