Abstract
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 level1,2,3. 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.
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Acknowledgements
We thank D. Hay, S. Orlando and L.J. Maltais for critical reading of the manuscript; W. Deng for assistance with the manuscript; J. Dobeck for histological assistance; and R. Kent and S.-I. A. Liao for statistical analysis assistance. This work was supported by NIH grants DE-07378 (P.S.) and AR44741 (Y.-P.L.).
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Li, YP., Chen, W., Liang, Y. et al. Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification. Nat Genet 23, 447–451 (1999). https://doi.org/10.1038/70563
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DOI: https://doi.org/10.1038/70563
