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

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, Ana Victoria Lechuga-Vieco, Mei Tian, Jian Qing Mi, Kwee Yong, Qing Zhong, Claire M. Edwards, Anna Katharina SimonNicole J. Horwood

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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.

Original languageEnglish
Article number7868
Number of pages18
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - 22 Dec 2022

Keywords

  • FACTOR-KAPPA-B
  • RECEPTOR ACTIVATOR
  • OSTEOCLAST DIFFERENTIATION
  • SIGNAL-TRANSDUCTION
  • MULTIPLE-MYELOMA
  • INHIBITORS
  • VIRUS
  • TRIAL
  • HYDROXYCHLOROQUINE
  • OSTEOPROTEGERIN

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