Oral Presentation ANZBMS-MEPSA-ANZORS 2022

Sugar transporter Slc37a2 regulates bone metabolism via a dynamic tubular lysosomal network in osteoclasts (#11)

Amy Ribet 1 , Pei Ying Ng 1 , Qiang Guo 1 , Benjamin H Mullin 2 , Jamie W.Y Tan 1 , Euphemie Landao-Bassonga 1 , Sébastien Stephens 3 , Kai Chen 1 , Laila Abudulai 1 4 , Maike Bollen 4 5 , Edward T.T.T. Nguyen 1 , Jasreen Kular 1 , John M Papadimitriou 6 , Kent Søe 7 8 , Rohan D. Teasdale 9 , Jiake Xu 1 , Robert G. Parton 10 , Hiroshi Takanayagi 11 , Nathan J. Pavlos 1
  1. School of Biomedical Science, UWA, CRAWLEY, WA, Australia
  2. Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Perth, WA, Australia
  3. School of Medicine and Dentistry, Griffith University, Southport, QLD, Australia
  4. Centre for Microscopy Analysis and Characterisation, UWA, CRAWLEY, WA, Australia
  5. School of Molecular Science, UWA, CRAWLEY, WA, Australia
  6. PathWest Laboratory Medicine , CRAWLEY, WA, Australia
  7. Pathology Research Unit, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
  8. Department of Pathology, Odense University Hospital, Odense, Denmark
  9. School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
  10. Institute for Molecular Biosciences and Centre for Microscopy and Microanalysis, , The University of Queensland, St Lucia, QLD, Australia
  11. Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan

Bone-digesting osteoclasts harbour specialized lysosome-related organelles termed secretory lysosomes (SLs). SLs store cathepsin K and give rise to the osteoclast ruffled border (RB) upon fusion with the bone-oriented plasmalemma. Despite serving as a membrane precursor for RB genesis, and therefore fertile grounds for the discovery of new homeostatic regulators of bone mass, our understanding of the molecular composition of osteoclast SLs remains incomplete. Here, by integrating the organelle proteome of enriched SLs isolated from mouse osteoclasts with human GWAS of estimated bone mineral density, we identified member a2 of the solute carrier 37 family (Slc37a2) as a new SL sugar transporter associated with the physiological regulation of bone mass. In situ, we demonstrate that among bone-lineage cells, Slc37a2 expression is restricted to osteoclasts where it localizes to the limiting membrane of SLs and the RB. Using live-cell microscopy, we unexpectedly find that Slc37a2+ve SLs adopt a dynamic tubular organization in osteoclasts that radiates throughout the cytoplasm and fuses with the bone-apposed plasmalemma. Physiologically, bones from mice lacking Slc37a2 (Slc37a2KO) exhibit a profound increase in trabecular bone mass, which affords protection against age-associated bone loss. At the cellular level, this dramatic increase in bone mass is driven primarily by impaired bone resorption by osteoclasts coupled with imbalanced remodelling-based osteoblastic bone formation. Mechanistically, SLs in Slc37a2KO osteoclasts are engorged and dysfunctional owing to disturbances in the luminal export of monosaccharide sugars, a prerequisite necessary for SL organelle resolution, tubulation and delivery to the RB. Accordingly, Slc37a2KO osteoclasts exhibit disturbances in RB maturation and decreased delivery and secretion of cathepsin K. Altogether, our findings: (i) unmask Slc37a2 as a SL sugar transporter critical for physiological bone metabolism, (ii) highlight previously unappreciated plasticity of the osteoclast’s specialized lysosome-related organelle(s) and; (iii) posit Slc37a2 as potential therapeutic target for metabolic bone diseases.