Abstract
ABSTRACTOsteoclasts are multinucleated cells that are characterized by their unique ability to resorb large quantities of bone. Therefore, they are frequently the target of therapeutic interventions to ameliorate bone loss. In an adult organism, osteoclasts derive from hematopoietic stem cells and differentiate into osteoclasts within a multistep process under the influence of macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL). Historically, the osteoclast life cycle has been defined as linear, whereby lineage‐committed mononuclear precursors fuse to generate multinucleated highly specialized and localized bone phagocytic cells, which then undergo apoptosis within weeks. Recent advances through lineage tracing, single cell RNA sequencing, parabiosis, and intravital imaging approaches have challenged this dogma, revealing they have greater longevity and the capacity to circulate and undergo cell recycling. Indeed, these new insights highlight that under homeostatic conditions very few incidences of osteoclast apoptosis occur. More importantly, as we revisit the formation and fate of the osteoclast, novel methods to target osteoclast biology in bone pathology and regeneration are emerging. This review briefly summarizes the historical life cycle of osteoclasts and highlights recent discoveries made through advanced methodologies, which have led to a paradigm shift in osteoclast biology. These findings are discussed in light of both existing and emerging bone targeted therapeutics, bone pathologies, and communication between osteoclasts and cells resident in bone or at distant sites. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Highlights
Bone and mineral homeostasis is critically dependent on the balance of bone resorption via osteoclasts and bone formation via osteoblasts
1990s and eventually led to the development of a RANKLneutralizing antibody, denosumab, which today is one of the most potent therapeutics to block osteoclasts and bone resorption and decrease fracture risk in patients with osteoporosis.[4]. Despite decades of research into their origin, formation, function, and fate, new insights into these unique cells continue to emerge adding more insights into their communication with other bone-residing cells, their capacity to repopulate from circulating cells and even recycle themselves, all in order to maintain a previously unappreciated longevity and avoid cell death
JBMR® Plus an important source of cytokines necessary to induce osteoclast differentiation was pivotal for the emergence of the concept of “coupling”, even before macrophage colony-stimulating factor (M-CSF) and RANKL were identified as those critical factors.[3,39] Coupling refers to the coordinated actions of osteoclasts and osteoblasts and their intimate communication with each other.[40]. As such, genetic or therapeutic suppression of osteoclasts leads to a reduction in osteoblast activity and bone formation as well, whereas stimulation of osteoblasts results in enhanced osteoclast activity
Summary
Bone and mineral homeostasis is critically dependent on the balance of bone resorption via osteoclasts and bone formation via osteoblasts.
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