4/1/2023 0 Comments Atlasti overviewUnexpectedly, using live cell imaging, we reveal that Slc37a2 + SLs exist as a hitherto unreported but highly dynamic tubular lysosomal network in osteoclasts that radiates throughout the cytoplasm and fuses with the bone-lining plasmalemma. Here, to expand the molecular landscape of osteoclast SLs, we systematically surveyed the proteome of enriched SLs isolated from murine osteoclasts and identified Slc37a2 as a candidate SL transporter. Yet despite their critical importance, our understanding of the molecular anatomy and spatiotemporal organization of osteoclast SLs remains limited. The ruffled border, together with the juxtaposed resorption lacuna, is therefore considered a giant digestive ‘extracellular LRO’ 16.Īs a precursor membrane for ruffled border genesis, SLs represent fertile grounds for the discovery of new homeostatic regulators of bone mass and thus potential anti-resorptive drug targets. At the same time, the coalescence of SL membranes with the ventral plasmalemma enriches the ruffled border with nanoscale bone-digesting machinery, including V-ATPases 15 and ClC-7 13, which cooperatively acidify the resorptive space to dissolve bone mineral. Fusion of SLs with the bone-apposed plasmalemma discharges cathepsin K into the underlying resorptive microenvironment to digest collagenous (Type 1a) bone matrix. Osteoclast SLs store the acidic hydrolase cathepsin K 8 and tartrate-resistant acid phosphatase 9 and are compositionally and functionally defined by the presence of several endo-lysosomal membrane proteins, namely LAMP1/2 10, Rab7 11, the a3 V-ATPase proton pump subunit 12, chloride channel ClC-7 13, TI-VAMP/VAMP7 and synaptotagmin 7 14. Unlike conventional lysosomes, which traditionally serve as intracellular depots for the degradation and recycling of endogenous and exogenous biomolecules 6, LROs are ‘hybrid organelles’ that share features of both late-endosomes and lysosomes coupled with exocytic functions 7. Ruffled border formation involves the polarized fusion of specialized lysosomal-related organelles (LROs), termed secretory lysosomes (SLs), with the bone-apposed plasmalemma 4, 5. These multinucleated giants degrade bone via the ruffled border, a villous-like plasma membrane domain circumscribed by an actin ring that serves as the osteoclast’s unique ‘resorptive apparatus’. Osteoclasts are bone-digesting cells that play a central role in skeletal bone growth and metabolism and underscore pathologies such as osteoporosis and osteopetrosis 1, 2, 3. Thus, Slc37a2 is a physiological component of the osteoclast’s unique secretory organelle and a potential therapeutic target for metabolic bone diseases. 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. 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. Here, using organelle-resolution proteomics, we identify member a2 of the solute carrier 37 family (Slc37a2) as a SL sugar transporter. Yet, the molecular composition and spatiotemporal organization of SLs remains incompletely understood. SLs store cathepsin K and serve as a membrane precursor to the ruffled border, the osteoclast’s ‘resorptive apparatus’. Osteoclasts are giant bone-digesting cells that harbor specialized lysosome-related organelles termed secretory lysosomes (SLs). Nature Communications volume 14, Article number: 906 ( 2023) Sugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts
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