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Vacuolar proton pump H+-adenosine triphosphatases (V-ATPases) play an important role in osteoclast function. Further understanding of the cellular and molecular mechanisms of V-ATPase inhibition is vital for the development of anti-resorptive drugs specifically targeting osteoclast V-ATPases. In this study, we observed that bafilomycin A1, a naturally-occurring inhibitor of V-ATPases, increased the protein level of SQSTM1/p62, a known negative regulator of osteoclast formation. Consistently, we found that bafilomycin A1 diminishes the intracellular accumulation of the acidotropic probe lysotracker in osteoclast-like cells; indicative of reduced acidification. Further, bafilomycin A1 inhibits osteoclast formation with attenuation of cell fusion and multi-nucleation of osteoclast-like cells during osteoclast differentiation. Taken together, these data indicate that bafilomycin A1 attenuates osteoclast differentiation in part via increased levels of SQSTM1/p62 protein, providing further mechanistic insight into the effect of V-ATPase inhibition in osteoclasts. J. Cell. Biochem. 117: 1464–1470, 2016. © 2015 Wiley Periodicals, Inc.