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, Alexander Corr, Sean Warren, Maté Biro, Natalie C Butterfield, Siobhan E Guilfoyle, Davide Komla-Ebri, Michael R G Dack, Hannah F DewhurstJohn G Logan, Yongxiao 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, 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

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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.

Original languageEnglish
Pages (from-to)1330-1347.e13
JournalCell
Volume184
Issue number5
Early online date25 Feb 2021
DOIs
Publication statusPublished - 04 Mar 2021
Externally publishedYes

Keywords

  • RANKL
  • cell fission
  • cellular recycling
  • denosumab
  • macrophage
  • Osteoclast
  • Osteomorph
  • osteoporosis
  • osteoprotegerin
  • skeletal dysplasia

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