PT  - JOURNAL ARTICLE
AU  - Houfu Leng
AU  - Hanlin Zhang
AU  - Linsen Li
AU  - Shuhao Zhang
AU  - Yanping Wang
AU  - Adel Ersek
AU  - Emma Morris
AU  - Erdinc Sezgin
AU  - Yi-Hsuan Lee
AU  - Yunsen Li
AU  - Jianqing Mi
AU  - Qing Zhong
AU  - Claire Edwards
AU  - Anna Katharina Simon
AU  - Nicole J. Horwood
TI  - The glycosphingolipid inhibitor eliglustat inhibits autophagy in osteoclasts to increase bone mass and reduce myeloma bone disease
AID  - 10.1101/2021.02.05.429906
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.02.05.429906
4099  - http://biorxiv.org/content/early/2021/02/06/2021.02.05.429906.short
4100  - http://biorxiv.org/content/early/2021/02/06/2021.02.05.429906.full
AB  - Multiple myeloma (MM) is a fatal hematological malignancy, where the majority of patients are diagnosed with, or develop, destructive and debilitating osteolytic bone lesions. Current treatments for MM bone disease such as the bisphosphonate zoledronic acid can result in deleterious side effects at high doses. In this study, eliglustat, an FDA approved glycosphingolipid inhibitor, was shown to reduce MM bone disease in preclinical models of MM. Mechanistically, eliglustat alters the lipid composition and plasma membrane fluidity and acts as an autophagy flux inhibitor in bone-resorbing osteoclasts (OC). Autophagic degradation of the signaling molecule TRAF3 is key step in OC differentiation; this was prevented by eliglustat in OC precursors. In addition, eliglustat works depend on TRAF3 in vivo. Furthermore, the combination of eliglustat and zoledronic acid was found to have an additive effect to reduce MM bone disease, suggesting the potential for combination therapies that would allow for drug dose reductions. Taken together, this project identifies a novel mechanism in which glycosphingolipid inhibition reduces osteoclastogenesis via autophagy and highlights the translational potential of eliglustat for the treatment of bone loss disorders such as MM.One Sentence Summary Translational use of eliglustat as an autophagy inhibitor to limit bone lesions in multiple myeloma.Competing Interest StatementThe authors have declared no competing interest.