Sugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts

Pei Ying Ng, Amy B. P. Ribet, Qiang Guo, Benjamin H. Mullin, Jamie W. Y. Tan, Euphemie Landao-Bassonga, Sébastien Stephens, Kai Chen, Jinbo Yuan, Laila Abudulai, Maike Bollen, Edward T. T. T. Nguyen, Jasreen Kular, John M. Papadimitriou, Kent Søe, Rohan D. Teasdale, Jiake Xu, Robert G. Parton, Hiroshi Takayanagi and Nathan J. Pavlos ()
Additional contact information
Pei Ying Ng: The University of Western Australia
Amy B. P. Ribet: The University of Western Australia
Qiang Guo: The University of Western Australia
Benjamin H. Mullin: The University of Western Australia
Jamie W. Y. Tan: The University of Western Australia
Euphemie Landao-Bassonga: The University of Western Australia
Sébastien Stephens: Griffith University
Kai Chen: The University of Western Australia
Jinbo Yuan: The University of Western Australia
Laila Abudulai: The University of Western Australia
Maike Bollen: The University of Western Australia
Edward T. T. T. Nguyen: The University of Western Australia
Jasreen Kular: The University of Western Australia
John M. Papadimitriou: PathWest Laboratory Medicine WA
Kent Søe: University of Southern Denmark
Rohan D. Teasdale: The University of Queensland
Jiake Xu: The University of Western Australia
Robert G. Parton: The University of Queensland
Hiroshi Takayanagi: The University of Tokyo
Nathan J. Pavlos: The University of Western Australia

Nature Communications, 2023, vol. 14, issue 1, 1-23

Abstract: Abstract Osteoclasts are giant bone-digesting cells that harbor specialized lysosome-related organelles termed secretory lysosomes (SLs). SLs store cathepsin K and serve as a membrane precursor to the ruffled border, the osteoclast’s ‘resorptive apparatus’. Yet, the molecular composition and spatiotemporal organization of SLs remains incompletely understood. Here, using organelle-resolution proteomics, we identify member a2 of the solute carrier 37 family (Slc37a2) as a SL sugar transporter. We demonstrate in mice that Slc37a2 localizes to the SL limiting membrane and that these organelles adopt a hitherto unnoticed but dynamic tubular network in living osteoclasts that is required for bone digestion. Accordingly, mice lacking Slc37a2 accrue high bone mass owing to uncoupled bone metabolism and disturbances in SL export of monosaccharide sugars, a prerequisite for SL delivery to the bone-lining osteoclast plasma membrane. Thus, Slc37a2 is a physiological component of the osteoclast’s unique secretory organelle and a potential therapeutic target for metabolic bone diseases.

Date: 2023
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DOI: 10.1038/s41467-023-36484-2

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