Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification
Copyright policy )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.
- Massachusetts General Hospital United States
- Harvard University United States
- Forest Institute United States
Male, Mice, Knockout, Vacuolar Proton-Translocating ATPases, Osteoclasts, Hydrogen-Ion Concentration, Proton Pumps, Kidney, Mice, Inbred C57BL, Mice, Proton-Translocating ATPases, Phenotype, Liver, Osteopetrosis, Animals, Female, Tissue Distribution, RNA, Messenger, Bone Resorption, Extracellular Space
Male, Mice, Knockout, Vacuolar Proton-Translocating ATPases, Osteoclasts, Hydrogen-Ion Concentration, Proton Pumps, Kidney, Mice, Inbred C57BL, Mice, Proton-Translocating ATPases, Phenotype, Liver, Osteopetrosis, Animals, Female, Tissue Distribution, RNA, Messenger, Bone Resorption, Extracellular Space
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