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 sho
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Roles of Slit Ligands and Their Roundabout (Robo) Family of Receptors in Bone Remodeling Tomoaki Niimi Abstract
Slit guidance ligands (Slits) and their roundabout (Robo) family of receptors are wellknown 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
T. Niimi (*) Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan e-mail: [email protected]
(NELL) proteins that are novel ligands for Robo receptors. Keywords
Clastokine · Coupling factor · NELL1 · Osteoblast · Osteoclast
Abbreviations BMP EGFL FNIII GTPase Ig NELL RANK RANKL Robo Sema Slit
1
bone morphogenetic protein epidermal growth factor-like fibronectin type III guanosine triphosphatase immunoglobulin neural EGFL (NEL)-like receptor activator of nuclear factor-κ B RANK ligand roundabout semaphorin Slit guidance ligand
Introduction
Bone locally repeats ossification and bone resorption for a lifetime to build skeletal structures without changing its morphology and serves as a calcium reservoir to maintain calcium homeostasis. These turnover processes are called bone remodeling (Zaidi 2007). Bone remodeling is
T. Niimi
carried out by temporary structures known as the basic multicellular units (BMUs) that are composed of two main cell types: osteoclasts and osteoblasts (Sims and Martin 2015, 2020; Kenkre and Bassett 2018). The bone remodeling cycle begins with the activation of osteoclastic bone resorption. After the resorption phase is completed, osteoclasts disappear and osteoblast precursors are recruited to the bone surface, and this phase is called the reversal phase. The formation phase follows with osteoblasts laying down bone matrix until the resorbed bone is completely replaced by new bone. The same amount of bone that was resorbed by osteoclasts must be newly formed to maintain the balance between osteoclastic bone resorption and osteoblastic bone formation. A local coupling factor linking bone resorption to subsequent bone formation has long been proposed to explain the coordination of bone resorption and formation in BMUs (Sims and Martin 2020; Marti
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