Glycosphingolipid synthesis inhibition limits osteoclast activation and myeloma bone disease.
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.
Adel
A
Ersek
Ke
K
Xu
Aristotelis
A
Antonopoulos
Terry D
TD
Butters
Ana Espirito
AE
Santo
Youridies
Y
Vattakuzhi
Lynn M
LM
Williams
Katerina
K
Goudevenou
Lynett
L
Danks
Andrew
A
Freidin
Emmanouil
E
Spanoudakis
Simon
S
Parry
Maria
M
Papaioannou
Evdoxia
E
Hatjiharissi
Aristeidis
A
Chaidos
Dominic S
DS
Alonzi
Gabriele
G
Twigg
Ming
M
Hu
Raymond A
RA
Dwek
Stuart M
SM
Haslam
Irene
I
Roberts
Anne
A
Dell
Amin
A
Rahemtulla
Nicole J
NJ
Horwood
Anastasios
A
Karadimitris
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D005260:Female; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D065089:Glycoside Hydrolase Inhibitors / Q000494:pharmacology; D006028:Glycosphingolipids / Q000096:biosynthesis* / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010014:Osteolysis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
D065089:Glycoside Hydrolase Inhibitors; D006028:Glycosphingolipids; D053245:RANK Ligand; D048029:TNF Receptor-Associated Factor 6; C505689:Tnfsf11 protein, mouse; C519530:insulin-like growth factor-1, mouse; D017485:1-Deoxynojirimycin; D007334:Insulin-Like Growth Factor I; C059896:miglustat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases