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v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation
被引:441
作者:
Lee, Seoung-Hoon
Rho, Jaerang
Jeong, Daewon
Sul, Jai-Yoon
Kim, Taesoo
Kim, Nacksung
Kang, Ju-Seob
Miyamoto, Takeshi
Suda, Toshio
Lee, Sun-Kyeong
Pignolo, Robert J.
Koczon-Jaremko, Boguslawa
Lorenzo, Joseph
Choi, Yongwon
[1
]
机构:
[1] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Dept Neurosci, Philadelphia, PA 19104 USA
[3] Keio Univ, Sch Med, Dept Cell Differentiat & Orthoped Surg, Shinjuku Ku, Tokyo 1608582, Japan
[4] Univ Connecticut, Ctr Hlth, Dept Med, Div Endocrinol, Farmington, CT 06030 USA
[5] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA
[6] Yeungnam Univ, Coll Med, Dept Microbiol, Taegu 705717, South Korea
[7] Chonnam Natl Univ, Sch Med, Med Res Ctr Gene Regulat, Kwangju 501746, South Korea
[8] Hanyang Univ, Dept Pharmacol, Coll Med, Seoul 133791, South Korea
[9] Hanyang Univ, Inst Biomed Sci, Seoul 133791, South Korea
基金:
美国国家卫生研究院;
关键词:
D O I:
10.1038/nm1514
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
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(1,2). Fusion-mediated giant cell formation is critical for osteoclast maturation; without it, bone resorption is inefficient(2,3). 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) V-0 domain (Atp6v0d2)(4-7). 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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页码:1403 / 1409
页数:7
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