The Chloride/proton Antiporter ClC3 is Critical for Normal Bone Formation

Acid transport is required for bone synthesis by osteoblasts. The osteoblast basolateral surface extrudes acid by Na+/H+ exchange, but proton uptake is unclear. We found high expression of the Cl-/H+ exchanger ClC3 at the bone apical surface. This is not consistent with the known ClC3 function in vesicular chloride transport, but is consistent with Cldependency of H+ transport in osteoblast membranes. To determine whether this ClC3 functions in bone formation, we used ClC3 knockout animals, and closely-related ClC5 knockout animals: In vitro studies suggested that both ClC3 and ClC5 might support bone formation. Genotypes were confirmed by total exon sequences.