Osteoclasts (OCs) are bone-lining cells derived from the fusion of monocytic precursors. Their exclusive positioning in contact with bone enables OC differentiation and the remodeling of bone outgrowth. However, the guidance cues that osteoclast precursors (OCP) follow for positioning at the bone surface remain poorly characterized. We demonstrate that EBI2 (Gpr183) was abundantly expressed in OCPs, and that autocrine EBI2 signaling was necessary for differentiation into mature osteoclasts in vitro. The expression of EBI2 and its ligands suggested that EBI2 signaling regulates OCP motility. Time lapse microscopy of OCP differentiation revealed reduced velocity and displacement of EBI2-deficient OCPs and mature OCs in vitro. Mice deficient in EBI2 or EBI2-ligands were osteopetrotic under homeostasis, and were protected from osteoporosis induced by estrogen deficiency. As osteoblasts (OBs) control osteoclast differentiation we hypothesized that they also recruit OCPs to bone niches. Indeed, OBs expressed EBI2-ligand synthesis enzymes, Ch25h and Cyp7b1, and secreted EBI2 ligands in vitro. We further demonstrate that EBI2-deficient OCPs were unable to efficiently migrate towards bone, and differentiated into smaller sized osteoclasts in vivo. Remarkably, overexpression of EBI2 was sufficient for directing OCPs to bone surfaces. Combined, these studies revealed a novel EBI2 controlled bone marrow niche, and identified a new candidate for the treatment of bone disorders.
- Copyright © 2013 by The American Association of Immunologists, Inc.