Roles of Slit Ligands and Their Roundabout (Robo) Family of Receptors in Bone Remodeling

Slit guidance ligands (Slits) and their roundabout (Robo) family of receptors are well-known axon guidance molecules that were originally identified in Drosophila mutants with commissural axon pathfinding defects. However, Slit-Robo signaling has been shown to be involved in not only neurogenesis, but also the development of other organs such as the kidney and heart. Recently, it was also revealed that Slit-Robo signaling plays an important role in bone metabolism. For example, osteoclast-derived Slit3 plays an osteoprotective role by synchronously stimulating bone formation by osteoblasts and suppressing bone resorption by osteoclasts through Robo receptors expressed on osteoblastic and osteoclastic cell lineages, making it a potential therapeutic target for metabolic bone disorders. Furthermore, osteoblast-derived Slit3 promotes bone formation indirectly as a proangiogenic factor. This review summarizes the recent progress on defining the roles of the Slit-Robo signaling in bone metabolism, and discusses the possible roles of the interaction between Robo and neural epidermal growth factor-like (NEL)-like (NELL) proteins that are novel ligands for Robo receptors.