essential for calpain-dependent regulation of the actin cytoskeleton in osteoclasts

per-missive for apical acid secretion while preventing cytoplasmicalkalinization. Here we show that osteoclast-targeted deletion inmice of solute carrier family 4 anion exchanger member 2 (Slc4a2)results in osteopetrosis. We further demonstrate a previously un-recognized consequence of SLC4A2 loss of function in the osteo-clast: dysregulation of calpain-dependent podosome disassembly,leading to abnormal actin belt formation, cell spreading, and mi-gration. Rescue of SLC4A2-deficient osteoclasts with functionallydefined mutants of SLC4A2 indicates regulation of actin cytoskel-etal reorganization by anion-exchange activity and intracellularpH, independent of SLC4A2’s long N-terminal cytoplasmic domain.These data suggest that maintenance of intracellular pH in osteo-clasts through anion exchange regulates the actin superstructuresrequired for bone resorption.