Nature Medicine
- 12, 1403 - 1409 (2006)
Published online: 26 November 2006; | doi:10.1038/nm1514
v-ATPase V0 subunit d2–deficient mice exhibit impaired osteoclast fusion and increased bone formationSeoung-Hoon Lee1, Jaerang Rho1, 6, Daewon Jeong1, 6, Jai-Yoon Sul2, Taesoo Kim1, Nacksung Kim1, 6, Ju-Seob Kang1, 6, Takeshi Miyamoto3, Toshio Suda3, Sun-Kyeong Lee4, Robert J Pignolo5, Boguslawa Koczon-Jaremko4, Joseph Lorenzo4 & Yongwon Choi11
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. 2
Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. 3
Department of Cell Differentiation and Orthopedic Surgery, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan. 4
Division of Endocrinology, Department of Medicine, MC-5456, University of Connecticut Health Center, Farmington, Connecticut 06030, USA. 5
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. 6
Present Address: Department of Microbiology, Chungnam National University, Daejon 305-764, Korea (J.R.), Department of Microbiology, Yeungnam University College of Medicine, 317-1 Daemyungdong, Namgu, Daegu 705-717, Korea (D.J.), Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Korea (N.K.) and Department of Pharmacology, College of Medicine and Institute of Biomedical Science, Hanyang University, Seoul 133-791, Korea (J.-S.K.).
Correspondence should be addressed to ychoi3@mail.med.upenn.edu 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 cells1,
2. Fusion-mediated giant cell formation is critical for osteoclast maturation; without it, bone resorption is inefficient2,
3. 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) V0 domain (Atp6v0d2)4,
5,
6,
7. 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.
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