Blocking glycosphingolipid production alters autophagy in osteoclasts and improves myeloma bone disease

ABSTRACT

Glycosphingolipids (GSLs) are key constituents of membrane bilayers playing a role in structural integrity, cell signalling in microdomains, endosomes and lysosomes, and cell death pathways. Conversion of ceramide into GSLs is controlled by GCS (glucosylceramide synthase) and inhibitors of this enzyme for the treatment of lipid storage disorders and specific cancers. With a diverse range of functions attributed to GSLs, the ability of the GSC inhibitor, eliglustat, to reduce myeloma bone disease was investigated. In pre-clinical models of multiple myeloma, osteoclast-driven bone loss was reduced by eliglustat in a mechanistically separate manner to zoledronic acid, a bisphosphonate that prevents osteoclast-mediated bone destruction. Autophagic degradation of TNF receptor-associated factor 3 (TRAF3), a key step for osteoclast differentiation, was inhibited by eliglustat as evidenced by TRAF3 lysosomal and cytoplasmic accumulation. By altering GSL composition, eliglustat prevented lysosomal degradation whilst exogenous addition of missing GSLs rescued TRAF3 degradation to restore osteoclast formation in bone marrow cells from myeloma patients. This work highlights the clinical potential of eliglustat as a therapy for myeloma bone disease. Furthermore, using eliglustat as a lysosomal inhibitor in osteoclasts may widen its therapeutic uses to other bone disorders such as bone metastasis, osteoporosis and inflammatory bone loss.

KEYWORDS:

• Autophagy
• glycosphingolipid
• TRAF3
• osteoclast
• multiple myeloma

Abbreviations

ER	=	Endoplasmic reticulum
GCS	=	Glucosylceramide synthase
GlcCer	=	Glucosylceramide
GSLs	=	Glycosphingolipids
NF-κB	=	Nuclear factor kappa B
RANK	=	Receptor activator of NF-κB
RANKL	=	Receptor activator of NF-κB ligand
TRAF3	=	TNF receptor-associated factor 3
TRAF6	=	TNF receptor-associated factor 6
UGCG	=	UDP-glucose ceramide glucosyltransferase

Disclosure statement

H.L, A.K.S. and N.J.H declare no competing interests.

Additional information

Funding

University of Oxford Medical and Life Sciences Translational Fund MC_PC_17174 and MC_PC_18059 from Wellcome ISSF fund and MRC confidence in concept to A.K.S. and H.L. Wellcome Trust Fund 220784/Z/20/Z to A.K.S. Versus Arthritis grant 20372 to N.J.H. Genzyme grant GZ-2015-11433 to N.J.H. China Scholarship Council to H.L.