@article{9673aa70bbbc4aeebb882e228d7b37fd,
title = "Sugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts",
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.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.",
keywords = "Plasma-membrane, Cathepsin-k, Ruffled border, H+-atpase, Osteopetrosis, Resorption, Proteins, Cell, Differentiation, Identification",
author = "Ng, {Pei Ying} and Ribet, {Amy B.P.} and Qiang Guo and Mullin, {Benjamin H.} and Tan, {Jamie W.Y.} and Euphemie Landao-Bassonga and S{\'e}bastien Stephens and Kai Chen and Jinbo Yuan and Laila Abudulai and Maike Bollen and Nguyen, {Edward T.T.T.} and Jasreen Kular and Papadimitriou, {John M.} and Kent S{\o}e and Teasdale, {Rohan D.} and Jiake Xu and Parton, {Robert G.} and Hiroshi Takayanagi and Pavlos, {Nathan J.}",
note = "Funding Information: We thank Rob Day and Alex Haynes (Royal Perth Hospital, WA) for their technical assistance with the biomechanical testing studies, Lisa Griffiths (PathWest, WA) for performing electron microscopy on bone tissue, Daniel Yagoub for proteomics assistance, James Rae for assistance with electron microscopy of cultured cells and Natalie Sims (St. Vincent{\textquoteright}s Institute, VIC) for insightful discussions. We are also indebted to Michael S. Marks (University of Pennsylvania, USA) and Alistair N. Hume (The University of Nottingham, UK) and Roland Baron (Harvard School of Dental Medicine, USA) for the provision of plasmids. This work was supported by NHMRC Project funding APP1143921 to N.J.P., R.D., and J.X., NHMRC grants APP1140064 and APP1150083 and fellowship APP1156489 to R.G.P., an NHMRC grant APP2003629 and Department of Health Western Australia Merit Award 1186046 to B.M., an Arthritis Australia and HJ & GJ Mackenzie Grant (N.J.P. and P.Y.N.), and a Faculty of Health and Medical Sciences Research Grant Scheme (SE Ohman Medical Research Fund to N.J.P. and P.Y.N.). A.B.P.R. is supported by Australian Government Research Training Program Scholarship. The authors acknowledge the facilities, and the scientific and technical assistance of Microscopy Australia at the Centre for Microscopy, Characterization & Analysis, The University of Western Australia, a facility funded by the University, State, and Commonwealth Government and of the Microscopy Australia Research Facility at the Centre for Microscopy and Microanalysis at The University of Queensland. N.J.P. and K.S. are supported by COST Action GEMSTONE CA18139 (European Cooperation in Science and Technology). Funding Information: We thank Rob Day and Alex Haynes (Royal Perth Hospital, WA) for their technical assistance with the biomechanical testing studies, Lisa Griffiths (PathWest, WA) for performing electron microscopy on bone tissue, Daniel Yagoub for proteomics assistance, James Rae for assistance with electron microscopy of cultured cells and Natalie Sims (St. Vincent{\textquoteright}s Institute, VIC) for insightful discussions. We are also indebted to Michael S. Marks (University of Pennsylvania, USA) and Alistair N. Hume (The University of Nottingham, UK) and Roland Baron (Harvard School of Dental Medicine, USA) for the provision of plasmids. This work was supported by NHMRC Project funding APP1143921 to N.J.P., R.D., and J.X., NHMRC grants APP1140064 and APP1150083 and fellowship APP1156489 to R.G.P., an NHMRC grant APP2003629 and Department of Health Western Australia Merit Award 1186046 to B.M., an Arthritis Australia and HJ & GJ Mackenzie Grant (N.J.P. and P.Y.N.), and a Faculty of Health and Medical Sciences Research Grant Scheme (SE Ohman Medical Research Fund to N.J.P. and P.Y.N.). A.B.P.R. is supported by Australian Government Research Training Program Scholarship. The authors acknowledge the facilities, and the scientific and technical assistance of Microscopy Australia at the Centre for Microscopy, Characterization & Analysis, The University of Western Australia, a facility funded by the University, State, and Commonwealth Government and of the Microscopy Australia Research Facility at the Centre for Microscopy and Microanalysis at The University of Queensland. N.J.P. and K.S. are supported by COST Action GEMSTONE CA18139 (European Cooperation in Science and Technology). Publisher Copyright: {\textcopyright} 2023, Crown.",
year = "2023",
month = dec,
doi = "10.1038/s41467-023-36484-2",
language = "English",
volume = "14",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group - Macmillan Publishers",
number = "1",
}