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

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Item Type:Article
Title:Modulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease
Creators Name:Leng, H. and Zhang, H. and Li, L. and Zhang, S. and Wang, Y. and Chavda, S.J. and Galas-Filipowicz, D. and Lou, H. and Ersek, A. and Morris, E.V. and Sezgin, E. and Lee, Y.H. and Li, Y. and Lechuga-Vieco, A.V. and Tian, M. and Mi, J.Q. and Yong, K. and Zhong, Q. and Edwards, C.M. and Simon, A.K. and Horwood, N.J.
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.
Keywords:Bone, Macroautophagy, Molecular Medicine, Myeloma, Translational Research
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:7868
Date:22 December 2022
Official Publication:https://doi.org/10.1038/s41467-022-35358-3
PubMed:View item in PubMed

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