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

Author

Listed:
  • Houfu Leng

    (University of Oxford)

  • Hanlin Zhang

    (University of Oxford)

  • Linsen Li

    (Shanghai Jiao Tong University School of Medicine)

  • Shuhao Zhang

    (University of Oxford
    Carnegie Mellon University)

  • Yanping Wang

    (Soochow University)

  • Selina J. Chavda

    (University College London)

  • Daria Galas-Filipowicz

    (University College London)

  • Hantao Lou

    (University of Oxford)

  • Adel Ersek

    (University of East Anglia)

  • Emma V. Morris

    (University of Oxford)

  • Erdinc Sezgin

    (Karolinska Institute
    MRC Weatherall Institute of Molecular Medicine, MRC Human Immunology Unit)

  • Yi-Hsuan Lee

    (University of Oxford
    University of East Anglia)

  • Yunsen Li

    (Soochow University)

  • Ana Victoria Lechuga-Vieco

    (University of Oxford)

  • Mei Tian

    (Fudan University)

  • Jian-Qing Mi

    (RuiJin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Kwee Yong

    (University College London)

  • Qing Zhong

    (Shanghai Jiao Tong University School of Medicine)

  • Claire M. Edwards

    (University of Oxford
    University of Oxford)

  • Anna Katharina Simon

    (University of Oxford)

  • Nicole J. Horwood

    (University of Oxford
    University of East Anglia)

Abstract

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.

Suggested Citation

  • Houfu Leng & Hanlin Zhang & Linsen Li & Shuhao Zhang & Yanping Wang & Selina J. Chavda & Daria Galas-Filipowicz & Hantao Lou & Adel Ersek & Emma V. Morris & Erdinc Sezgin & Yi-Hsuan Lee & Yunsen Li & , 2022. "Modulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35358-3
    DOI: 10.1038/s41467-022-35358-3
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    References listed on IDEAS

    as
    1. Alice C. Newman & Alain J. Kemp & Yvette Drabsch & Christian Behrends & Simon Wilkinson, 2017. "Autophagy acts through TRAF3 and RELB to regulate gene expression via antagonism of SMAD proteins," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
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