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 Simon () and Nicole J. Horwood ()
Additional contact information
Houfu Leng: University of Oxford
Hanlin Zhang: University of Oxford
Linsen Li: Shanghai Jiao Tong University School of Medicine
Shuhao Zhang: University of Oxford
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
Yi-Hsuan Lee: University of Oxford
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
Anna Katharina Simon: University of Oxford
Nicole J. Horwood: University of Oxford

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-35358-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35358-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-35358-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().