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 Dewhurst; John 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; 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

doi:10.1016/j.cell.2021.02.002

Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption

Cell. 2021 Mar 4;184(5):1330-1347.e13. doi: 10.1016/j.cell.2021.02.002. Epub 2021 Feb 25.

Authors

Michelle M McDonald¹, Weng Hua Khoo¹, Pei Ying Ng², Ya Xiao³, Jad Zamerli³, Peter Thatcher³, Wunna Kyaw⁴, Karrnan Pathmanandavel⁴, Abigail K Grootveld⁴, Imogen Moran⁴, Danyal Butt⁴, Akira Nguyen⁴, Alexander Corr¹, Sean Warren⁵, Maté Biro⁶, Natalie C Butterfield⁷, Siobhan E Guilfoyle⁷, Davide Komla-Ebri⁷, Michael R G Dack⁷, Hannah F Dewhurst⁷, John G Logan⁷, Yongxiao Li⁸, Sindhu T Mohanty¹, Niall Byrne¹, Rachael L Terry¹, Marija K Simic¹, Ryan Chai³, Julian M W Quinn¹, Scott E Youlten³, Jessica A Pettitt³, David Abi-Hanna¹, Rohit Jain⁹, Wolfgang Weninger¹⁰, Mischa Lundberg¹¹, Shuting Sun¹², Frank H Ebetino¹², Paul Timpson⁵, Woei Ming Lee⁸, Paul A Baldock¹, Michael J Rogers¹, Robert Brink¹³, Graham R Williams⁷, J H Duncan Bassett⁷, John P Kemp¹⁴, Nathan J Pavlos², Peter I Croucher¹⁵, Tri Giang Phan¹⁶

Affiliations

¹ Healthy Ageing Theme, Garvan Institute of Medical Research, Sydney, NSW, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia.
² Bone Biology & Disease Laboratory, School of Biomedical Sciences, University of Western Australia, Nedlands, WA, Australia.
³ Healthy Ageing Theme, Garvan Institute of Medical Research, Sydney, NSW, Australia.
⁴ Immunology Theme, Garvan Institute of Medical Research, Sydney, NSW, Australia.
⁵ Cancer, Garvan Institute of Medical Research, Sydney, NSW, Australia.
⁶ EMBL Australia, Single Molecule Science Node, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
⁷ Molecular Endocrinology Laboratory, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK.
⁸ John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
⁹ Immune Imaging Program, Centenary Institute, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
¹⁰ Immune Imaging Program, Centenary Institute, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Department of Dermatology, Medical University of Vienna, Vienna, Austria.
¹¹ The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba, QLD, Australia; Transformational Bioinformatics, Commonwealth Scientific and Industrial Research Organisation, Sydney, NSW, Australia.
¹² Biovinc, Pasadena, CA, USA.
¹³ St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia; Immunology Theme, Garvan Institute of Medical Research, Sydney, NSW, Australia.
¹⁴ The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba, QLD, Australia; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
¹⁵ Healthy Ageing Theme, Garvan Institute of Medical Research, Sydney, NSW, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia. Electronic address: p.croucher@garvan.org.au.
¹⁶ St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia; Immunology Theme, Garvan Institute of Medical Research, Sydney, NSW, Australia. Electronic address: t.phan@garvan.org.au.

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.

Keywords: RANKL; cell fission; cellular recycling; denosumab; macrophage; osteoclast; osteomorph; osteoporosis; osteoprotegerin; skeletal dysplasia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Bone Resorption / metabolism
Bone Resorption / pathology*
Cell Fusion
Cells, Cultured
Humans
Macrophages / cytology
Mice
Osteochondrodysplasias / drug therapy
Osteochondrodysplasias / genetics
Osteochondrodysplasias / metabolism
Osteochondrodysplasias / pathology
Osteoclasts / metabolism
Osteoclasts / pathology*
RANK Ligand / metabolism*
Signal Transduction

Substances

RANK Ligand
Tnfsf11 protein, mouse

Grants and funding

WT_/Wellcome Trust/United Kingdom