Modulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease
Year: 2022
Type: article
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.
Source: Nature Communications
Authors: 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, Nicole J. Horwood
Institutions: University of Oxford, Kennedy Institute of Rheumatology, Shanghai Jiao Tong University, Carnegie Mellon University, Soochow University, University College London, Ludwig Cancer Research, University of East Anglia, Science for Life Laboratory, Karolinska Institutet, MRC Weatherall Institute of Molecular Medicine, MRC Human Immunology Unit, Fudan University, Ruijin Hospital, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,890
Funders: University of Rochester, Wellcome Trust, International Seafood Sustainability Foundation, University of Oxford, Hong Kong Baptist University, National Natural Science Foundation of China, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, China Scholarship Council, Science for Life Laboratory, Versus Arthritis, Blood Cancer UK, Ruijin Hospital, Medical Center, University of Rochester, Medical Research Council
Awards: G1440928906, G2193249121, G2505578151, Proteostasis and Autophagy in Immune Senescence, G3246855288, G3412331035, G3906557818, Correlative cytometry to measure biophysical properties of cells in health and disease, G6478192530, G7346215257, G7432965211, University of Oxford Confidence in Concept – Round 7, G8975826080, G9000067200
OpenAlex ID: W4312072312