Fusion of preosteoclasts to generate multinucleated osteoclasts is defective in the absence of DC-STAMP (right).

Bone-resorbing osteoclasts can't pull together in the absence of dendritic cell–specific transmembrane protein (DC-STAMP), according to new data from Yagi and colleagues (page 345). Without this receptor, osteoclast precursor cells cannot fuse with one another. The failure to fuse cripples the bone resorbing function of the cells, causing osteopetrosis (increased bone mass).

DC-STAMP is a seven-transmembrane–spanning receptor that was originally isolated from dendritic cells (DCs). The ligand for DC-STAMP and its function on DCs are unknown, but this receptor was recently found on osteoclasts and shown to be required for these cells to develop from their macrophage precursors.

Yagi and colleagues now refine these data by showing that multinucleated osteoclasts were completely absent in the bones of mice lacking DC-STAMP, although osteoclast development was intact. The DC-STAMP–deficient mice suffered from mild osteopetrosis, as mononucleated osteoclasts can still resorb bone. Whether DC-STAMP triggers fusion directly or triggers the expression of other fusion-inducing receptors remains to be determined.

The absence of DC-STAMP also inhibited the formation of foreign body giant cells—products of macrophage fusion that dispose of foreign bodies in tissues. Although the mechanism is not yet known, DC-STAMP may function as a fusion coreceptor in a fashion analogous to the fusion of HIV with target cells, which depends on seven-transmembrane–spanning chemokine receptors (see commentary from Vignery, on page 337).