Formation of multinucleated bone-resorbing osteoclasts results from activation of the receptor activated NF-κB ligand (RANKL)-receptor activated NF-κB (RANK) signaling pathway in primary bone marrow macrophages and a macrophage cell line (RAW 264.7). Osteoclasts, through bone remodeling, are key participants in the homeostatic regulation of calcium and phosphate levels within the body. Microarray analysis using Gene Expression Dynamic Inspector (GEDI) clustering software indicated that osteoclast differentiation is correlated with an increase in xenotropic and polytropic virus receptor 1 (XPR1) mRNA transcripts. XPR1 is a receptor of the xenotropic and polytropic murine leukemia virus and homolog of yeast Syg1 and plant Pi transporter PHO1. Quantitative PCR was used to validate the up-regulation of XPR1 message following RANKL stimulation in both primary bone marrow cells and a macrophage cell line. Immunostaining for the XPR1 protein showed that there is translocation of XPR1 to the membranes of the sealing zone in mature osteoclasts. This study is the first to demonstrate that the expression of retro-viral receptor, XPR1, is regulated by RANKL-RANK signaling. © 2010 Elsevier Inc.