v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation.
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.
Lee
Seoung-Hoon
SH
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Rho
Jaerang
J
Jeong
Daewon
D
Sul
Jai-Yoon
JY
Kim
Taesoo
T
Kim
Nacksung
N
Kang
Ju-Seob
JS
Miyamoto
Takeshi
T
Suda
Toshio
T
Lee
Sun-Kyeong
SK
Pignolo
Robert J
RJ
Koczon-Jaremko
Boguslawa
B
Lorenzo
Joseph
J
Choi
Yongwon
Y
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*
D020033:Protein Isoforms; D017494:Proton Pumps; D053245:RANK Ligand; D016173:Macrophage Colony-Stimulating Factor; D025262:Vacuolar Proton-Translocating ATPases