학술논문
Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption
Document Type
Report
Author
McDonald, Michelle M.; Khoo, Weng Hua; Ng, Pei Ying; Xiao, Ya; Zamerli, Jad; Thatcher, Peter; Kyaw, Wunna; Pathmanandavel, Karrnan; Grootveld, Abigail K.; Moran, Imogen; Butt, Danyal; Nguyen, Akira; Corr, Alexander; Warren, Sean; Biro, Mate; Butterfield, Natalie C.; Guilfoyle, Siobhan E.; Komla-Ebri, Davide; Dack, Michael R.G.; Dewhurst, Hannah F.; Logan, John G.; Li, Yongxiao; Mohanty, Sindhu T.; Byrne, Niall; Terry, Rachael L.; Simic, Marija K.; Chai, Ryan; Quinn, Julian M.W.; Youlten, Scott E.; Pettitt, Jessica A.; Abi-Hanna, David; Jain, Rohit; Weninger, Wolfgang; Lundberg, Mischa; Sun, Shuting; Ebetino, Frank H.; Timpson, Paul; Lee, Woei Ming; Baldock, Paul A.; Rogers, Michael J.; Brink, Robert; Williams, Graham R.; Bassett, J.H. Duncan; Kemp, John P.; Pavlos, Nathan J.; Croucher, Peter I.; Phan, Tri Giang
Source
Cell. March 4, 2021, Vol. 184 Issue 5, 1330
Subject
Language
English
ISSN
0092-8674
Abstract
Keywords osteomorph; osteoclast; cell fission; cellular recycling; macrophage; RANKL; osteoprotegerin; denosumab; osteoporosis; skeletal dysplasia Highlights * Osteoclasts fission into daughter cells called osteomorphs * Osteomorphs fuse and recycle back into osteoclasts * Osteomorph upregulated genes control bone structure and function in mice * Osteomorph upregulated genes are implicated in rare and common bone diseases in humans Summary 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.