title: Deficiency ofATP6V1HCauses Bone Loss by Inhibiting Bone Resorption and Bone Formation through the TGF-β1 Pathway.
abstract: Vacuolar-type H+-ATPase (V-ATPase) is a highly conserved, ancient enzyme that couples the energy of ATP hydrolysis to proton transport across vesicular and plasma membranes of eukaryotic cells. Previously reported mutations of various V-ATPase subunits are associated with increased bone density. We now show that haploinsufficiency for the H subunit of the V1domain (ATP6V1H) is associated with osteoporosis in humans and mice. A genome-wide SNP array analysis of 1625 Han Chinese found that 4 of 15 tag SNPs (26.7%) withinATP6V1Hwere significantly associated with low spine bone mineral density.Atp6v1h+/-knockout mice generated by the CRISPR/Cas9 technique had decreased bone remodeling and a net bone matrix loss.Atp6v1h+/-osteoclasts showed impaired bone formation and increased bone resorption. The increased intracellular pH ofAtp6v1h+/-osteoclasts downregulated TGF-β1 activation, thereby reducing induction of osteoblast formation but the bone mineralization was not altered. However, bone formation was reduced more than bone resorption. Our data provide evidence that partial loss of ATP6V1H function results in osteoporosis/osteopenia. We propose that defective osteoclast formation triggers impaired bone formation by altering bone remodeling. In the future, ATP6V1H might, therefore, serve as a target for the therapy of osteoporosis.
authors.affiliation: State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Oral Diseases, Department of Oral Biology, Clinic of Oral Rare and Genetic Diseases, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, People's Republic of China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Duan
authors.affiliation: State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Oral Diseases, Department of Oral Biology, Clinic of Oral Rare and Genetic Diseases, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, People's Republic of China.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Oral Diseases, Department of Oral Biology, Clinic of Oral Rare and Genetic Diseases, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, People's Republic of China.
authors.forename: Xueni
authors.initials: X
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Oral Diseases, Department of Oral Biology, Clinic of Oral Rare and Genetic Diseases, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, People's Republic of China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Oral Diseases, Department of Oral Biology, Clinic of Oral Rare and Genetic Diseases, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, People's Republic of China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Oral Diseases, Department of Oral Biology, Clinic of Oral Rare and Genetic Diseases, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, People's Republic of China.
authors.forename: Tielin
authors.initials: T
authors.lastname: Yang
authors.affiliation: School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, USA.
authors.forename: Hongwen
authors.initials: H
authors.lastname: Deng
mesh_terms: D000818:Animals; D001862:Bone Resorption; D002681:China; D020022:Genetic Predisposition to Disease; D006801:Humans; D018345:Mice, Knockout; D010012:Osteogenesis; D010024:Osteoporosis / Q000235:genetics* / Q000503:physiopathology*; D020641:Polymorphism, Single Nucleotide; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*
chemical_list: D053773:Transforming Growth Factor beta1; C567969:ATP6V1H protein, human; D025262:Vacuolar Proton-Translocating ATPases
keywords: ATP6V1H; CRISPR/Cas9; OPG.; RANKL; TGF-β1; V-ATPase; osteoclasts; osteoporosis; pH