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; 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

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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236 Citations (Scopus)

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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 language	English
Pages (from-to)	1330-1347.e13
Journal	Cell
Volume	184
Issue number	5
Early online date	25 Feb 2021
DOIs	https://doi.org/10.1016/j.cell.2021.02.002
Publication status	Published - 04 Mar 2021
Externally published	Yes

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2021.02.002Licence: CC BY

Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption
Copyright 2021 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 12.2 MBLicence: CC BY

236 Citations
1 Comment/debate

Correction: Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption
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. & 26 others, 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., 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., 01 Apr 2021, In: Cell. 184, 7, p. 1940 1 p.
Research output: Contribution to journal › Comment/debate › peer-review

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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., ... Phan, T. G. (2021). Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell, 184(5), 1330-1347.e13. https://doi.org/10.1016/j.cell.2021.02.002

@article{baa512b8d526408682258aab813554ad,

title = "Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption",

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",

author = "McDonald, {Michelle M} and Khoo, {Weng Hua} and Ng, {Pei Ying} and Ya Xiao and Jad Zamerli and Peter Thatcher and Wunna Kyaw and Karrnan Pathmanandavel and Grootveld, {Abigail K} and Imogen Moran and Danyal Butt and Akira Nguyen and Alexander Corr and Sean Warren and Mat{\'e} Biro and Butterfield, {Natalie C} and Guilfoyle, {Siobhan E} and Davide Komla-Ebri and Dack, {Michael R G} and Dewhurst, {Hannah F} and Logan, {John G} and Yongxiao Li and Mohanty, {Sindhu T} and Niall Byrne and Terry, {Rachael L} and Simic, {Marija K} and Ryan Chai and Quinn, {Julian M W} and Youlten, {Scott E} and Pettitt, {Jessica A} and David Abi-Hanna and Rohit Jain and Wolfgang Weninger and Mischa Lundberg and Shuting Sun and Paul Timpson and Lee, {Woei Ming} and Baldock, {Paul A} and Rogers, {Michael J} and Robert Brink and Williams, {Graham R} and Bassett, {J H Duncan} and Kemp, {John P} and Pavlos, {Nathan J} and Croucher, {Peter I} and Phan, {Tri Giang}",

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doi = "10.1016/j.cell.2021.02.002",

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McDonald, MM, Khoo, WH, Ng, PY, Xiao, Y, Zamerli, J, Thatcher, P, Kyaw, W, Pathmanandavel, K, Grootveld, AK, Moran, I, Butt, D, Nguyen, A, Corr, A, Warren, S, Biro, M, Butterfield, NC, Guilfoyle, SE, Komla-Ebri, D, Dack, MRG, Dewhurst, HF, Logan, JG, Li, Y, Mohanty, ST, Byrne, N, Terry, RL, Simic, MK, Chai, R, Quinn, JMW, Youlten, SE, Pettitt, JA, Abi-Hanna, D, Jain, R, Weninger, W, Lundberg, M, Sun, S, Timpson, P, Lee, WM, Baldock, PA, Rogers, MJ, Brink, R, Williams, GR, Bassett, JHD, Kemp, JP, Pavlos, NJ, Croucher, PI & Phan, TG 2021, 'Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption', Cell, vol. 184, no. 5, pp. 1330-1347.e13. https://doi.org/10.1016/j.cell.2021.02.002

TY - JOUR

T1 - Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption

AU - McDonald, Michelle M

AU - Khoo, Weng Hua

AU - Ng, Pei Ying

AU - Xiao, Ya

AU - Zamerli, Jad

AU - Thatcher, Peter

AU - Kyaw, Wunna

AU - Pathmanandavel, Karrnan

AU - Grootveld, Abigail K

AU - Moran, Imogen

AU - Butt, Danyal

AU - Nguyen, Akira

AU - Corr, Alexander

AU - Warren, Sean

AU - Biro, Maté

AU - Butterfield, Natalie C

AU - Guilfoyle, Siobhan E

AU - Komla-Ebri, Davide

AU - Dack, Michael R G

AU - Dewhurst, Hannah F

AU - Logan, John G

AU - Li, Yongxiao

AU - Mohanty, Sindhu T

AU - Byrne, Niall

AU - Terry, Rachael L

AU - Simic, Marija K

AU - Chai, Ryan

AU - Quinn, Julian M W

AU - Youlten, Scott E

AU - Pettitt, Jessica A

AU - Abi-Hanna, David

AU - Jain, Rohit

AU - Weninger, Wolfgang

AU - Lundberg, Mischa

AU - Sun, Shuting

AU - Timpson, Paul

AU - Lee, Woei Ming

AU - Baldock, Paul A

AU - Rogers, Michael J

AU - Brink, Robert

AU - Williams, Graham R

AU - Bassett, J H Duncan

AU - Kemp, John P

AU - Pavlos, Nathan J

AU - Croucher, Peter I

AU - Phan, Tri Giang

PY - 2021/3/4

Y1 - 2021/3/4

N2 - 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.

AB - 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.

KW - RANKL

KW - cell fission

KW - cellular recycling

KW - denosumab

KW - macrophage

KW - Osteoclast

KW - Osteomorph

KW - osteoporosis

KW - osteoprotegerin

KW - skeletal dysplasia

U2 - 10.1016/j.cell.2021.02.002

DO - 10.1016/j.cell.2021.02.002

M3 - Article

C2 - 33636130

SN - 0092-8674

VL - 184

SP - 1330-1347.e13

JO - Cell

JF - Cell

IS - 5

ER -

Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption

Abstract

Keywords

UN SDGs

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Research output

Correction: Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption

Cite this