v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation.

Nat Med 2006 Dec 26;12(12):1403-9. Epub 2006 Nov 26.

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

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.

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http://dx.doi.org/10.1038/nm1514DOI Listing
December 2006
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References

(Supplied by CrossRef)

MC Walsh et al.
Annu. Rev. Immunol. 2006

SL Teitelbaum et al.
Science 2000

M Yagi et al.
J. Exp. Med. 2005

T Nishi et al.
J. Biol. Chem. 2003

GH Sun-Wada et al.
Gene 2003

AN Smith et al.
Gene 2002

J Rho et al.
DNA Cell Biol. 2002

T Nishi et al.
Nat. Rev. Mol. Cell Biol. 2002

TH Stevens et al.
Annu. Rev. Cell Dev. Biol. 1997

T Suda et al.
Methods Enzymol. 1997

Y Kadono et al.
EMBO Rep. 2005

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