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

• Published in: Nature communications Vol. 13; no. 1; pp. 7868 - 18
• Main Authors: Leng, Houfu, Zhang, Hanlin, Li, Linsen, Zhang, Shuhao, Wang, Yanping, Chavda, Selina J., Galas-Filipowicz, Daria, Lou, Hantao, Ersek, Adel, Morris, Emma V., Sezgin, Erdinc, Lee, Yi-Hsuan, Li, Yunsen, Lechuga-Vieco, Ana Victoria, Tian, Mei, Mi, Jian-Qing, Yong, Kwee, Zhong, Qing, Edwards, Claire M., Simon, Anna Katharina, Horwood, Nicole J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.12.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 101/58; 13/1; 13/106; 13/31; 13/95; 14/19; 14/28; 14/63; 631/80/39/2346; 692/308/575; 692/4017; 692/4023/1671/63; 692/699/1541/1990/804; Autophagy; Bone diseases; Bone Diseases - drug therapy; Bone Diseases - metabolism; Bone lesions; Bone loss; Bone marrow; Ceramide glucosyltransferase; Degradation; Differentiation; FDA approval; Glycosphingolipids; Glycosphingolipids - metabolism; Humanities and Social Sciences; Humans; Lesions; Malignancy; Medicin och hälsovetenskap; Metabolism; multidisciplinary; Multiple myeloma; Multiple Myeloma - pathology; Osteoclastogenesis; Osteoclasts - metabolism; Osteolysis; Patients; Plasma cells; Quality of Life; Science; Science (multidisciplinary); TNF Receptor-Associated Factor 3 - metabolism; Zoledronic acid
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35358-3

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. Here, the authors show that the glycosylceramide synthesis inhibitor and FDA approved drug Eliglustat inhibits autophagic degradation of TRAF3 which is a key step for osteoclast differentiation and thereby improves myeloma bone lesions.