Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption
Open accessAbstract
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.
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RANKL inhibition by DMAB results in osteomorph accumulation.
“Since RANKL inhibition by DMAB results in osteomorph accumulation,257 the reconstitution of RANKL signaling, as occurs upon DMAB discontinuation, can activate massive bone resorption over a very short time scale, leading to rebound fractures.260”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [257]
Osteoclasts are recycled into osteomorphs.
“second, osteoclasts have recently been shown to be recycled into osteomorphs.”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [257]
Osteomorphs are highly motile osteoclast daughter cells that remain in the adjacent bone marrow and retain the ability to fuse back into functional osteoclasts.
“Osteomorphs have been described as highly motile osteoclast daughter cells that remain in the adjacent bone marrow and retain the ability to fuse back into functional osteoclasts.257”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [257]
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Sialylation of TLR2 initiates osteoclast fusion
Dou, C., Zhen, G., Dan, Y., Wan, M., Limjunyawong, N., & Cao, X. (2022) · Bone Research · doi:10.1038/s41413-022-00186-0 · Cited by 46 · see citing works
- Authors
- McDonald, M. M., Khoo, W. H., Ng, P. Y., Xiao, Y., Zamerli, J., Thatcher, P., Kyaw, W., Pathmanandavel, K., Grootveld, A. K., Moran, I., Butt, D., Nguyen, A., Corr, A., Warren, S., Biro, M., Butterfield, N. C., Guilfoyle, S. E., Komla-Ebri, D., Dack, M. R. G., Dewhurst, H. F., Logan, J. G., Li, Y., Mohanty, S. T., Byrne, N., Terry, R. L., Simic, M. K., Chai, R., Quinn, J. M. W., Youlten, S. E., Pettitt, J. A., Abi-Hanna, D., Jain, R., Weninger, W., Lundberg, M., Sun, S., Ebetino, F. H., Timpson, P., Lee, W. M., Baldock, P. A., Rogers, M. J., Brink, R., Williams, G. R., Bassett, J. H. D., Kemp, J. P., Pavlos, N. J., Croucher, P. I., & Phan, T. G.
- Affiliations
- Garvan Institute of Medical Research (AU)
- The University of Western Australia (AU)
- UNSW Sydney (AU)
- Imperial College London (GB)
- Australian National University (AU)
- The University of Sydney (AU)
- Commonwealth Scientific and Industrial Research Organisation (AU)
- BioVinc (United States) (US)
- The University of Queensland (AU)
- Corresponding author
- Croucher, Peter I.
- Phan, Tri Giang
- ORCID
- McDonald, Michelle M.
- Khoo, Weng Hua
- Ng, Pei Ying
- Xiao, Ya
- Kyaw, Wunna
- Pathmanandavel, Karrnan
- Grootveld, Abigail K.
- Butt, Danyal
- Nguyen, Akira
- Corr, Alexander
- Warren, Sean
- Biro, Maté
- 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.
- Weninger, Wolfgang
- Lundberg, Mischa
- Sun, Shuting
- Ebetino, Frank H.
- Timpson, Paul
- Lee, Woei Ming
- Rogers, Michael J.
- Brink, Robert
- Williams, Graham R.
- Bassett, J.H. Duncan
- Kemp, John P.
- Pavlos, Nathan J.
- Croucher, Peter I.
- Phan, Tri Giang
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-03
- Volume
- 184
- Issue
- 5
- Pages
- 1330-1347.e13
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7938889
- OpenAlex
- W3133129058
- Cited by
- 433
- References
- 87
- Citations by year
- 2026: 72 · 2025: 78 · 2024: 80 · 2023: 87 · 2022: 72 · 2021: 39 · 2020: 5
- FWCI
- 21.80
- Type
- journal article
- Language
- en
- Update notices
- erratum (2021-04-01)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion, cc-by)
- ANU Open Research (Australian National University) (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by)
- Funders
- Wellcome Trust
- NHMRC
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
- Keywords
- osteoclasts, bone resorption, RANKL, osteoclastogenesis, intravital imaging, single-cell RNA sequencing, bone mineral density
- MeSH terms
- Animals, Bone Resorption, Cell Fusion, Cells, Cultured, Humans, Macrophages, Osteochondrodysplasias, Osteoclasts, Signal Transduction, Apoptosis, Mice, RANK Ligand
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