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

• Published in: Nature communications Vol. 14; no. 1; p. 906
• Main Authors: Ng, Pei Ying, Ribet, Amy B. P., Guo, Qiang, Mullin, Benjamin H., Tan, Jamie W. Y., Landao-Bassonga, Euphemie, Stephens, Sébastien, Chen, Kai, Yuan, Jinbo, Abudulai, Laila, Bollen, Maike, Nguyen, Edward T. T. T., Kular, Jasreen, Papadimitriou, John M., Søe, Kent, Teasdale, Rohan D., Xu, Jiake, Parton, Robert G., Takayanagi, Hiroshi, Pavlos, Nathan J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.02.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/109; 14; 38; 38/35; 45; 45/43; 631/136/815/817; 631/443/63; 631/80/313/1624; 631/80/642/1624; 64/60; 692/163/2743/316/800; 82/58; Animals; Biological Transport; Bone and Bones - metabolism; Bone diseases; Bone mass; Bone Resorption - metabolism; Bone turnover; Cathepsin K; Cell Membrane - metabolism; Chemical composition; Digestion; Humanities and Social Sciences; Lysosomes; Lysosomes - metabolism; Membranes; Metabolism; Mice; Monosaccharides; multidisciplinary; Organelles; Osteoclasts; Osteoclasts - metabolism; Proteomics; Science; Science (multidisciplinary); Sugar; Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36484-2

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. Despite the importance of osteoclast secretory lysosomes in bone digestion, the proteins that regulate them remain ill defined. Here, the authors identify Slc37a2 as a secretory lysosome sugar transporter that is required for maintenance of skeletal bone mass.