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SLC4A2-mediated Cl⁻/HCO₃⁻ exchange activity is essential for calpain-dependent regulation of the actin cytoskeleton in osteoclasts

Bone remodeling requires osteoclasts to generate and maintain an acidified resorption compartment between the apical membrane and the bone surface to solubilize hydroxyapatite crystals within the bone matrix. This acidification process requires (i) apical proton secretion by a vacuolar H ⁺-ATPase, (...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2013-02, Vol.110 (6), p.2163-2168
Main Authors: Coury, Fabienne, Zenger, Serhan, Stewart, Andrew K., Stephens, Sebastien, Neff, Lynn, Tsang, Kelly, Shull, Gary E., Alper, Seth L., Baron, Roland, Aliprantis, Antonios O.
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container_title Proceedings of the National Academy of Sciences - PNAS
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creator Coury, Fabienne
Zenger, Serhan
Stewart, Andrew K.
Stephens, Sebastien
Neff, Lynn
Tsang, Kelly
Shull, Gary E.
Alper, Seth L.
Baron, Roland
Aliprantis, Antonios O.
description Bone remodeling requires osteoclasts to generate and maintain an acidified resorption compartment between the apical membrane and the bone surface to solubilize hydroxyapatite crystals within the bone matrix. This acidification process requires (i) apical proton secretion by a vacuolar H ⁺-ATPase, (ii) actin cytoskeleton reorganization into a podosome belt that forms a gasket to restrict lacunar acid leakage, and (iii) basolateral chloride uptake and bicarbonate extrusion by an anion exchanger to provide Cl ⁻ permissive for apical acid secretion while preventing cytoplasmic alkalinization. Here we show that osteoclast-targeted deletion in mice of solute carrier family 4 anion exchanger member 2 (Slc4a2) results in osteopetrosis. We further demonstrate a previously unrecognized consequence of SLC4A2 loss of function in the osteoclast: dysregulation of calpain-dependent podosome disassembly, leading to abnormal actin belt formation, cell spreading, and migration. Rescue of SLC4A2-deficient osteoclasts with functionally defined mutants of SLC4A2 indicates regulation of actin cytoskeletal reorganization by anion-exchange activity and intracellular pH, independent of SLC4A2’s long N-terminal cytoplasmic domain. These data suggest that maintenance of intracellular pH in osteoclasts through anion exchange regulates the actin superstructures required for bone resorption.
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subjects Actin Cytoskeleton - metabolism
Actins
Animals
Anion Transport Proteins - deficiency
Anion Transport Proteins - genetics
Anion Transport Proteins - metabolism
Anions
Antiporters - deficiency
Antiporters - genetics
Antiporters - metabolism
Biological Sciences
Bone resorption
Bones
Calpain - metabolism
Cells, Cultured
Chloride-Bicarbonate Antiporters - deficiency
Chloride-Bicarbonate Antiporters - genetics
Chloride-Bicarbonate Antiporters - metabolism
Gene expression regulation
Hydrogen-Ion Concentration
Life span
Mice
Mice, Knockout
Mutant Proteins - genetics
Mutant Proteins - metabolism
Osteoclasts
Osteoclasts - metabolism
Osteoclasts - pathology
Osteopetrosis
Osteopetrosis - genetics
Osteopetrosis - metabolism
Osteopetrosis - pathology
Phenotypes
SLC4A Proteins
title SLC4A2-mediated Cl⁻/HCO₃⁻ exchange activity is essential for calpain-dependent regulation of the actin cytoskeleton in osteoclasts
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