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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.
47 Authors
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
Enabling scientific discoveries that improve human health