TY - JOUR
T1 - Sugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts
AU - Ng, Pei Ying
AU - Ribet, Amy B.P.
AU - Guo, Qiang
AU - Mullin, Benjamin H.
AU - Tan, Jamie W.Y.
AU - Landao-Bassonga, Euphemie
AU - Stephens, Sébastien
AU - Chen, Kai
AU - Yuan, Jinbo
AU - Abudulai, Laila
AU - Bollen, Maike
AU - Nguyen, Edward T.T.T.
AU - Kular, Jasreen
AU - Papadimitriou, John M.
AU - Søe, Kent
AU - Teasdale, Rohan D.
AU - Xu, Jiake
AU - Parton, Robert G.
AU - Takayanagi, Hiroshi
AU - Pavlos, Nathan J.
N1 - 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’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’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:
© 2023, Crown.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85148736809&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-36484-2
DO - 10.1038/s41467-023-36484-2
M3 - Article
C2 - 36810735
AN - SCOPUS:85148736809
VL - 14
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 906
ER -