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.
View: Text | PDF
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

×
Problems with a PDF?

This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.

Having trouble reading a PDF?

PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.

Having trouble saving a PDF?

Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.

Having trouble printing a PDF?

  1. Try printing one page at a time or to a newer printer.
  2. Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
  3. Make sure you are using the latest version of Adobe's Acrobat Reader.

Supplemental data - Download (1.65 MB)

Advertisement