title: SLC4A2-mediated Cl-/HCO3- exchange activity is essential for calpain-dependent regulation of the actin cytoskeleton in osteoclasts.
abstract: 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.
authors: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors: Fabienne
authors: F
authors: Coury
authors: Serhan
authors: S
authors: Zenger
authors: Andrew K
authors: AK
authors: Stewart
authors: Sebastien
authors: S
authors: Stephens
authors: Lynn
authors: L
authors: Neff
authors: Kelly
authors: K
authors: Tsang
authors: Gary E
authors: GE
authors: Shull
authors: Seth L
authors: SL
authors: Alper
authors: Roland
authors: R
authors: Baron
authors: Antonios O
authors: AO
authors: Aliprantis
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D027321:Anion Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017920:Antiporters / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D002478:Cells, Cultured; D027963:Chloride-Bicarbonate Antiporters / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D051379:Mice; D018345:Mice, Knockout; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010022:Osteopetrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D064606:SLC4A Proteins
chemical_list: D027321:Anion Transport Proteins; D017920:Antiporters; D027963:Chloride-Bicarbonate Antiporters; D050505:Mutant Proteins; D064606:SLC4A Proteins; C579495:Slc4a2 protein, mouse; D002154:Calpain