Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption

Michelle M. McDonald, Weng Hua Khoo, Pei Ying Ng, Ya Xiao, Jad Zamerli, Peter Thatcher, Wunna Kyaw, Karrnan Pathmanandavel, Abigail K. Grootveld, Imogen Moran, Danyal Butt, Akira Nguyen, Sean Warren, Maté Biro, Natalie C. Butterfield, Siobhan E. Guilfoyle, Davide Komla-Ebri, Michael R.G. Dack, Hannah F. Dewhurst, John G. LoganYongxiao Li, Sindhu T. Mohanty, Niall Byrne, Rachael L. Terry, Marija K. Simic, Ryan Chai, Julian M.W. Quinn, Scott E. Youlten, Jessica A. Pettitt, David Abi-Hanna, Rohit Jain, Wolfgang Weninger, Mischa Lundberg, Shuting Sun, Frank H. Ebetino, Paul Timpson, Woei Ming Lee, Paul A. Baldock, Michael J. Rogers, Robert Brink, Graham R. Williams, J. H.Duncan Bassett, John P. Kemp, Nathan J. Pavlos, Peter I. Croucher*, Tri Giang Phan*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    213 Citations (Scopus)

    Abstract

    Osteoclasts are large multinucleated bone-resorbing cells formed by the fusion of monocyte/macrophage-derived precursors that are thought to undergo apoptosis once resorption is complete. Here, by intravital imaging, we reveal that RANKL-stimulated osteoclasts have an alternative cell fate in which they fission into daughter cells called osteomorphs. Inhibiting RANKL blocked this cellular recycling and resulted in osteomorph accumulation. Single-cell RNA sequencing showed that osteomorphs are transcriptionally distinct from osteoclasts and macrophages and express a number of non-canonical osteoclast genes that are associated with structural and functional bone phenotypes when deleted in mice. Furthermore, genetic variation in human orthologs of osteomorph genes causes monogenic skeletal disorders and associates with bone mineral density, a polygenetic skeletal trait. Thus, osteoclasts recycle via osteomorphs, a cell type involved in the regulation of bone resorption that may be targeted for the treatment of skeletal diseases. Tracking osteoclasts during cycles of fission and fusion reveals a transcriptionally distinct “osteomorph” population that are fusion competent, motile, and capable of forming osteoclasts that resorb bone.

    Original languageEnglish
    Pages (from-to)1330-1347.e13
    JournalCell
    Volume184
    Issue number5
    DOIs
    Publication statusPublished - 4 Mar 2021

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