Osteoclasts at Bone Remodeling: Order from Order

Osteoclasts are multinucleated bone-resorbing cells derived from the monocyte/macrophage lineage. The macrophage colony-stimulating factor/receptor activator of nuclear factor κB ligand (M-CSF/RANKL) signaling network governs the differentiation of precursor cells into fusion-competent mononucleated cells. Repetitive fusion of fusion-competent cells produces multinucleated osteoclasts. Osteoclasts are believed to die via apoptosis after bone resorption. However, recent studies have found that osteoclastogenesis in vivo proceeds by replacing the old nucleus of existing osteoclasts with a single newly differentiated mononucleated cell. Thus, the formation of new osteoclasts is minimal. Furthermore, the sizes of osteoclasts can change via cell fusion and fission in response to external conditions. On the other hand, osteoclastogenesis in vitro involves various levels of heterogeneity, including osteoclast precursors, mode of fusion, and properties of the differentiated osteoclasts. To better understand the origin of these heterogeneities and the plasticity of osteoclasts, we examine several processes of osteoclastogenesis in this review. Candidate mechanisms that create heterogeneity involve asymmetric cell division, osteoclast niche, self-organization, and mode of fusion and fission. Elucidation of the plasticity or fluctuation of the M-CSF/RANKL network should be an important topic for future researches.