title: Bafilomycin A1 Attenuates Osteoclast Acidification and Formation, Accompanied by Increased Levels of SQSTM1/p62 Protein.
abstract: 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.
authors.affiliation: Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.|School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, WA, Australia.
authors.forename: Sipin
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Laboratory for Molecular Endocrinology, Harry Perkins Institute of Medical Research and UWA Centre for Medical Research, The University of Western Australia, Crawley, WA, 6009, Australia.|Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Rea
authors.affiliation: School of Surgery, Centre of Orthopaedic Research, The University of Western Australia, Crawley, WA, 6009, Australia.
authors.forename: Taksum
authors.initials: T
authors.lastname: Cheng
authors.affiliation: School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, WA, Australia.
authors.forename: Hao Tian
authors.initials: HT
authors.lastname: Feng
authors.affiliation: Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, 6009, Australia.|School of Medicine and Pharmacology, The University of Western Australia, Crawley, WA, 6009, Australia.
authors.forename: John P
authors.initials: JP
authors.lastname: Walsh
authors.affiliation: Laboratory for Molecular Endocrinology, Harry Perkins Institute of Medical Research and UWA Centre for Medical Research, The University of Western Australia, Crawley, WA, 6009, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ratajczak
authors.affiliation: School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, WA, Australia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tickner
authors.affiliation: School of Surgery, Centre of Orthopaedic Research, The University of Western Australia, Crawley, WA, 6009, Australia.
authors.forename: Nathan
authors.initials: N
authors.lastname: Pavlos
authors.affiliation: Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Hua-Zi
authors.initials: HZ
authors.lastname: Xu
authors.affiliation: Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.|School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, WA, Australia.
authors.forename: Jiake
authors.initials: J
authors.lastname: Xu
mesh_terms: D000588:Amines / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D000067996:RAW 264.7 Cells; D000071456:Sequestosome-1 Protein / Q000378:metabolism*
chemical_list: D000588:Amines; D004791:Enzyme Inhibitors; D018942:Macrolides; C493330:Red DND-99; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C040929:bafilomycin A1; D002118:Calcium
keywords: ACIDIFICATION; BAFILOMYCIN A1; OSTEOCLASTOGENESIS; V-ATPases; p62