ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 5.12 | DOI: 10.1530/ey.18.5.12

Healthy Ageing Theme, Garvan Institute of Medical Research, Sydney, NSW, Australia; St. Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia.

Cell. 2021 Mar 4;184(5):1330–1347.e13 Abstract:

In brief: This paper reports an alternative cell fate for multinucleated, bone-resorbing osteoclasts and shows that they may undergo fission into smaller osteomorphs. The findings challenge the current dogma that osteoclasts primarily differentiate from hematopoietic progenitor cells and are terminally differentiated cells that are destined to undergo apoptosis after resorption is completed.

Comment: Fusion of monocyte/macrophage-derived precursor cells leads to the formation of osteoclasts, which are specialized bone-resorbing cells. These cells are thought to undergo apoptosis once bone resorption is complete. However, their life cycle in vivo is still elusive. Moreover, tracking osteoclast formation and fate in their native environment is challenging.

Here, McDonald et al. show, by intravital imaging of in vivo osteoclast dynamics, an alternative cell fate for RANKL-stimulated osteoclasts, which underwent fission into daughter cells called osteomorphs. They also found that this osteoclast recycling is regulated by RANKL signaling, as RANKL inhibition by decoy receptor led to accumulation of osteomorphs, which retain the ability to fuse into resorbing osteoclasts. Single-cell RNA sequencing of osteomorphs revealed that they are transcriptionally distinct from osteoclasts and macrophage precursors. Osteomorph upregulated genes control bone structure and function and may be implicated in the pathogenesis of rare monogenic skeletal dysplasias and common polygenic bone diseases.

In summary, this paper reports that osteoclasts recycle via osteomorphs, which are involved in regulation of bone resorption. These findings fundamentally challenge the current thinking of the fate and behavior of osteoclasts. They point towards novel mechanisms for the regulation of bone resorption and may lead to new therapeutic approaches for osteoporosis and other bone fragility disorders.

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