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The glycosphingolipid inhibitor eliglustat inhibits autophagy in osteoclasts to increase bone mass and reduce myeloma bone disease

Houfu Leng, Hanlin Zhang, Linsen Li, Shuhao Zhang, Yanping Wang, Adel Ersek, Emma Morris, Erdinc Sezgin, Yi-Hsuan Lee, Yunsen Li, Jianqing Mi, Qing Zhong, Claire Edwards, Anna Katharina Simon, Nicole J. Horwood
doi: https://doi.org/10.1101/2021.02.05.429906
Houfu Leng
1Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, UK, OX3 7FY
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Hanlin Zhang
1Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, UK, OX3 7FY
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Linsen Li
2Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
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Shuhao Zhang
1Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, UK, OX3 7FY
3Computational Biology Department, Carnegie Mellon University, Pittsburgh, Pennsylvania 15217, USA
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Yanping Wang
4Institutes of Biology and Medical Sciences, Soochow University, Suzhou, P.R. China
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Adel Ersek
1Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, UK, OX3 7FY
5Norwich Medical School, University of East Anglia, James Watson Road, Norwich, UK, NR4 7UQ
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Emma Morris
6Nuffield Dept. Of Surgical Sciences, Botnar Research Centre, University of Oxford, Old Road, Oxford, UK, OX3 7LD
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Erdinc Sezgin
7Science for Life Laboratory, Department of Women’s and Children’s Health, Karolinska Institute, Solna, Sweden
8MRC Weatherall Institute of Molecular Medicine, MRC Human Immunology Unit, OX3 9DS, Oxford, UK
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Yi-Hsuan Lee
1Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, UK, OX3 7FY
5Norwich Medical School, University of East Anglia, James Watson Road, Norwich, UK, NR4 7UQ
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Yunsen Li
4Institutes of Biology and Medical Sciences, Soochow University, Suzhou, P.R. China
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Jianqing Mi
9Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
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Qing Zhong
2Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
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Claire Edwards
6Nuffield Dept. Of Surgical Sciences, Botnar Research Centre, University of Oxford, Old Road, Oxford, UK, OX3 7LD
10Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Old Road, Oxford, UK, OX3 7LD
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Anna Katharina Simon
1Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, UK, OX3 7FY
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  • For correspondence: n.horwood@uea.ac.uk katja.simon@imm.ox.ac.uk
Nicole J. Horwood
1Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, UK, OX3 7FY
5Norwich Medical School, University of East Anglia, James Watson Road, Norwich, UK, NR4 7UQ
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  • For correspondence: n.horwood@uea.ac.uk katja.simon@imm.ox.ac.uk
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Abstract

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 Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 06, 2021.
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The glycosphingolipid inhibitor eliglustat inhibits autophagy in osteoclasts to increase bone mass and reduce myeloma bone disease
Houfu Leng, Hanlin Zhang, Linsen Li, Shuhao Zhang, Yanping Wang, Adel Ersek, Emma Morris, Erdinc Sezgin, Yi-Hsuan Lee, Yunsen Li, Jianqing Mi, Qing Zhong, Claire Edwards, Anna Katharina Simon, Nicole J. Horwood
bioRxiv 2021.02.05.429906; doi: https://doi.org/10.1101/2021.02.05.429906
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The glycosphingolipid inhibitor eliglustat inhibits autophagy in osteoclasts to increase bone mass and reduce myeloma bone disease
Houfu Leng, Hanlin Zhang, Linsen Li, Shuhao Zhang, Yanping Wang, Adel Ersek, Emma Morris, Erdinc Sezgin, Yi-Hsuan Lee, Yunsen Li, Jianqing Mi, Qing Zhong, Claire Edwards, Anna Katharina Simon, Nicole J. Horwood
bioRxiv 2021.02.05.429906; doi: https://doi.org/10.1101/2021.02.05.429906

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