Modulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease

Leng, Houfu, Zhang, Hanlin, Li, Linsen, Zhang, Shuhao, Wang, Yanping, Chavda, Selina J., Galas-Filipowicz, Daria, Lou, Hantao, Ersek, Adel, Morris, Emma V., Sezgin, Erdinc, Lee, Yi Hsuan, Li, Yunsen, Lechuga-Vieco, Ana Victoria, Tian, Mei, Mi, Jian Qing, Yong, Kwee, Zhong, Qing, Edwards, Claire M., Simon, Anna Katharina and Horwood, Nicole J. ORCID: (2022) Modulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease. Nature Communications, 13 (1). ISSN 2041-1723

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Patients with multiple myeloma, an incurable malignancy of plasma cells, frequently develop osteolytic bone lesions that severely impact quality of life and clinical outcomes. Eliglustat, a U.S. Food and Drug Administration-approved glucosylceramide synthase inhibitor, reduced osteoclast-driven bone loss in preclinical in vivo models of myeloma. In combination with zoledronic acid, a bisphosphonate that treats myeloma bone disease, eliglustat provided further protection from bone loss. Autophagic degradation of TRAF3, a key step for osteoclast differentiation, was inhibited by eliglustat as evidenced by TRAF3 lysosomal and cytoplasmic accumulation. Eliglustat blocked autophagy by altering glycosphingolipid composition whilst restoration of missing glycosphingolipids rescued autophagy markers and TRAF3 degradation thus restoring osteoclastogenesis in bone marrow cells from myeloma patients. This work delineates both the mechanism by which glucosylceramide synthase inhibition prevents autophagic degradation of TRAF3 to reduce osteoclastogenesis as well as highlighting the clinical translational potential of eliglustat for the treatment of myeloma bone disease.

Item Type: Article
Additional Information: Acknowledgements: The authors thank the patients who donated clinical samples used in this research. Zhenqiang Yao and Akram Ayoub from Brendan Boyce’s lab in University of Rochester Medical Center who provided scientific advice and prepared the TRAF3 KO mouse BM cells—it is greatly appreciated. We thank Xiaoxia Liu and members from Qing Zhong’s lab who helped with experiments. Confocal microscopy help from Christoffer Lagerholm, Senior Advanced Microscopy Manager in the Kennedy Institute of Rheumatology, is appreciated. Bin Xie, Pengjun Xi, and Jianqing Zheng from Kennedy Institute of Rheumatology, Zhu Liang from Target Discovery Institute, Jiahao Jiang and Jianwei Cui from Wellcome Centre for Human Genetics, University of Oxford; Jin Wang and Duohui Jing from Shanghai Ruijin Hospital; Ge Zhang from Hong Kong Baptist University all provided constructive comments. This work was supported by University of Oxford Medical and Life Sciences Translational Fund MC_PC_17174 and MC_PC_18059 from Wellcome ISSF fund and the MRC confidence in concept to A.K.S. and H. Leng; Wellcome Trust Fund 220784/Z/20/Z to A.K.S.; Versus Arthritis grant 20372 to N.J.H. and A.E.; Genzyme grant GZ-2015-11433 to N.J.H.; NSFC grant 91754205, 91957204, and 31771523 to Q.Z.; China Scholarship Council to H. Leng; China Scholarship Council-Nuffield Department of Medicine Scholarship and the Oxford-Elysium Prize Fellowship to H.Z.; Blood Cancer UK 17012 and 15026 to C.M.E. and E.V.M.; Knut and Alice Wallenberg Foundation, Swedish Research Council (2020-02682) and Wellcome Trust ISSF to E.S.; European Molecular Biology Organization Postdoctoral Fellowship (EMBO) ALTF115-2019 to A.V.L.V.
Uncontrolled Keywords: factor-kappa-b,receptor activator,osteoclast differentiation,signal-transduction,multiple-myeloma,inhibitors,virus,trial,hydroxychloroquine,osteoprotegerin,chemistry(all),biochemistry, genetics and molecular biology(all),general,physics and astronomy(all) ,/dk/atira/pure/subjectarea/asjc/1600
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Faculty of Science > School of Chemistry
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
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Depositing User: LivePure Connector
Date Deposited: 14 Apr 2023 12:35
Last Modified: 09 Mar 2024 10:32
DOI: 10.1038/s41467-022-35358-3


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