title: v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation.
abstract: Matrix-producing osteoblasts and bone-resorbing osteoclasts maintain bone homeostasis. Osteoclasts are multinucleated, giant cells of hematopoietic origin formed by the fusion of mononuclear pre-osteoclasts derived from myeloid cells. Fusion-mediated giant cell formation is critical for osteoclast maturation; without it, bone resorption is inefficient. To understand how osteoclasts differ from other myeloid lineage cells, we previously compared global mRNA expression patterns in these cells and identified genes of unknown function predominantly expressed in osteoclasts, one of which is the d2 isoform of vacuolar (H(+)) ATPase (v-ATPase) V(0) domain (Atp6v0d2). Here we show that inactivation of Atp6v0d2 in mice results in markedly increased bone mass due to defective osteoclasts and enhanced bone formation. Atp6v0d2 deficiency did not affect differentiation or the v-ATPase activity of osteoclasts. Rather, Atp6v0d2 was required for efficient pre-osteoclast fusion. Increased bone formation was probably due to osteoblast-extrinsic factors, as Atp6v02 was not expressed in osteoblasts and their differentiation ex vivo was not altered in the absence of Atp6v02. Our results identify Atp6v0d2 as a regulator of osteoclast fusion and bone formation, and provide genetic data showing that it is possible to simultaneously inhibit osteoclast maturation and stimulate bone formation by therapeutically targeting the function of a single gene.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Seoung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Jaerang
authors.initials: J
authors.lastname: Rho
authors.forename: Daewon
authors.initials: D
authors.lastname: Jeong
authors.forename: Jai-Yoon
authors.initials: JY
authors.lastname: Sul
authors.forename: Taesoo
authors.initials: T
authors.lastname: Kim
authors.forename: Nacksung
authors.initials: N
authors.lastname: Kim
authors.forename: Ju-Seob
authors.initials: JS
authors.lastname: Kang
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.forename: Sun-Kyeong
authors.initials: SK
authors.lastname: Lee
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Pignolo
authors.forename: Boguslawa
authors.initials: B
authors.lastname: Koczon-Jaremko
authors.forename: Joseph
authors.initials: J
authors.lastname: Lorenzo
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002459:Cell Fusion; D002478:Cells, Cultured; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D017494:Proton Pumps / Q000235:genetics*; D053245:RANK Ligand / Q000494:pharmacology; D025262:Vacuolar Proton-Translocating ATPases / Q000737:chemistry / Q000502:physiology*
chemical_list: D020033:Protein Isoforms; D017494:Proton Pumps; D053245:RANK Ligand; D016173:Macrophage Colony-Stimulating Factor; D025262:Vacuolar Proton-Translocating ATPases