DC-STAMP Is Essential for Osteoclastic Cell-cell Fusion

Objectives:Osteoclasts are multinuclear giant cells derived from hematopoietic stem cells in the presence of M-CSF and RANKL. The multinucleation of osteoclasts is induced by a cell-cell fusion of mononuclear osteoclasts. Recently, we have isolated DC-STAMP (Dendritic Cell Specific Transmenbrane Protein), a seven transmembrane protein, as an essential molecule for osteoclast cell-cell fusion, and that osteoclasts in DC-STAMP deficient mice showed complete lack of cell-cell fusion in osteoclasts. Since the osteoclast differentiation molecules such as TRAP and CathepsinK, and the transcriptional factors such as c-fos and NFATc1 were not suppressed in DC-STAMP deficient compared with wild-type osteoclasts, DC-STAMP is specifically required for osteoclast cell-cell fusion. However, it is not yet characterized the mechanisms of cell-cell fusion via DC-STAMP. Methods:Here we generated DC-STAMP transgenic mice under the control of an actin°°(CAG) promoter to express DC-STAMP ubiquitously in vivo.Results:The lack of cell-cell fusion in DC-STAMP-deficient osteoclasts was rescued by crossing with DC-STAMP transgenic mice and DC-STAMP expression was detected in various tissues of DC-STAMP Transgenic mice such as liver, muscle and brain, all of which do not express DC-STAMP physiologically. Interestingly, ectopic cell-cell fusion was not observed in liver and muscle, and the multinucleation of myotube was not stimulated by the forced expression of DC-STAMP in Transgenic mice. In in vitro osteoclast formation assay, the number of multinuclear cells as well as the number of nuclei in each multinuclear cell was significantly upregulated in osteoclasts of transgenic mice compared with that of wild-type littermates. The cell-cell fusion was not induced even in the cells derived from transgenic bone marrow in the presence of M-CSF alone, while the addition of RANKL in turn induced hyper¨Cmultinucleation of osteoclasts. Conclusions:Taken together our results suggest that DC-STAMP promotes cell-cell fusion in a tissue specific manner.