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; 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

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, Sean Warren, Maté Biro, Natalie C. Butterfield, Siobhan E. Guilfoyle, Davide Komla-Ebri, Michael R.G. Dack, Hannah F. Dewhurst, John G. LoganYongxiao 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

257 Citations (Scopus)

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. Tracking osteoclasts during cycles of fission and fusion reveals a transcriptionally distinct “osteomorph” population that are fusion competent, motile, and capable of forming osteoclasts that resorb bone.

Original language	English
Pages (from-to)	1330-1347.e13
Journal	Cell
Volume	184
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2021.02.002
Publication status	Published - 4 Mar 2021

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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., Warren, S., Biro, M., Butterfield, N. C., Guilfoyle, S. E., Komla-Ebri, D., Dack, M. R. G., Dewhurst, H. F., ... 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{801634b344f640a1b6353af0b0bd2ceb,

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. Tracking osteoclasts during cycles of fission and fusion reveals a transcriptionally distinct “osteomorph” population that are fusion competent, motile, and capable of forming osteoclasts that resorb bone.",

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 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 Ebetino, {Frank H.} 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}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = mar,

day = "4",

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

language = "English",

volume = "184",

pages = "1330--1347.e13",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "5",

}

McDonald, MM, Khoo, WH, Ng, PY, Xiao, Y, Zamerli, J, Thatcher, P, Kyaw, W, Pathmanandavel, K, Grootveld, AK, Moran, I, Butt, D, Nguyen, 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, Ebetino, FH, 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 - 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 - Ebetino, Frank H.

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. Tracking osteoclasts during cycles of fission and fusion reveals a transcriptionally distinct “osteomorph” population that are fusion competent, motile, and capable of forming osteoclasts that resorb bone.

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. Tracking osteoclasts during cycles of fission and fusion reveals a transcriptionally distinct “osteomorph” population that are fusion competent, motile, and capable of forming osteoclasts that resorb bone.

KW - RANKL

KW - cell fission

KW - cellular recycling

KW - denosumab

KW - macrophage

KW - osteoclast

KW - osteomorph

KW - osteoporosis

KW - osteoprotegerin

KW - skeletal dysplasia

UR - http://www.scopus.com/inward/record.url?scp=85101779008&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.02.002

DO - 10.1016/j.cell.2021.02.002

M3 - Article

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

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