Matrix-producing osteoblasts and bone-resorbing osteoclasts maintain bone homeostasis. Osteoclasts are multinucleated, giant cells of hematopoietic origin formed by the fusion of mononuclear preosteoclasts derived from myeloid cells. Fusion-mediated giant cell formation is critical for osteoclast maturation; without it, bone resorption is inefficient. One gene predominantly expressed in osteoclasts is the d2 isoform of vacuolar (H+) ATPase (v-ATPase) V0 domain (Atp6v0d2). What is the function of this protein?

To answer this question, Lee et al [1] inactivated this protein in mice. They observed that, in these animals, there was a 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, a function mandatory for acidification of the microenvironment of osteoclasts which allows solubilisation of hydroxyapatite. Rather, Atp6v0d2 was required for efficient preosteoclast fusion. Increased bone formation was probably due to osteoblast-extrinsic factors, produced by mutant osteoclasts or their immediate precursors, as Atp6v02 was not expressed in osteoblasts and their differentiation ex vivo was not altered in the absence of Atp6v02.

These 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.

1. Lee S-H et al. Nat Med. 2006;12:1403-1409.