Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification.
Solubilization of bone mineral by osteoclasts depends on the formation of an acidic extracellular compartment through the action of a V-proton pump that has not yet been characterized at the molecular level. We previously cloned a gene (Atp6i, for V-proton pump, H+ transporting (vacuolar proton pump) member I) encoding a putative osteoclast-specific proton pump subunit, termed OC-116kD (ref. 4). Here we show that targeted disruption of Atp6i in mice results in severe osteopetrosis. Atp6i-/- osteoclast-like cells (OCLs) lose the function of extracellular acidification, but retain intracellular lysosomal proton pump activity. The pH in Atp6i-/- liver lysosomes and proton transport in microsomes of Atp6i-/- kidney are identical to that in wild-type mice. Atp6i-/- mice exhibit a normal acid-base balance in blood and urine. Our results demonstrate that Atp6i is unique and necessary for osteoclast-mediated extracellular acidification.
Li
Y P
YP
Department of Cytokine Biology, The Forsyth Institute, Boston, Massachusetts, USA. ypli@forsyth.org
Chen
W
W
Liang
Y
Y
Li
E
E
Stashenko
P
P
D000818:Animals; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010022:Osteopetrosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D017494:Proton Pumps / Q000172:deficiency* / Q000235:genetics; D006180:Proton-Translocating ATPases / Q000172:deficiency* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution; D025262:Vacuolar Proton-Translocating ATPases
D017494:Proton Pumps; D012333:RNA, Messenger; D025262:Vacuolar Proton-Translocating ATPases; D006180:Proton-Translocating ATPases