Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease

Scott E. Youlten; John P. Kemp; John G. Logan; Elena J. Ghirardello; Claudio M. Sergio; Michael R.G. Dack; Siobhan E. Guilfoyle; Victoria D. Leitch; Natalie C. Butterfield; Davide Komla-Ebri; Ryan C. Chai; Alexander P. Corr; James T. Smith; Sindhu T. Mohanty; John A. Morris; Michelle M. McDonald; Julian M.W. Quinn; Amelia R. McGlade; Nenad Bartonicek; Matt Jansson; Konstantinos Hatzikotoulas; Melita D. Irving; Ana Beleza-Meireles; Fernando Rivadeneira; Emma Duncan; J. Brent Richards; David J. Adams; Christopher J. Lelliott; Robert Brink; Tri Giang Phan; John A. Eisman; David M. Evans; Eleftheria Zeggini; Paul A. Baldock; J. H.Duncan Bassett; Graham R. Williams; Peter I. Croucher

doi:10.1038/s41467-021-22517-1

Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease

Scott E. Youlten, John P. Kemp, John G. Logan, Elena J. Ghirardello, Claudio M. Sergio, Michael R.G. Dack, Siobhan E. Guilfoyle, Victoria D. Leitch, Natalie C. Butterfield, Davide Komla-Ebri, Ryan C. Chai, Alexander P. Corr, James T. Smith, Sindhu T. Mohanty, John A. Morris, Michelle M. McDonald, Julian M.W. Quinn, Amelia R. McGlade, Nenad Bartonicek, Matt JanssonKonstantinos Hatzikotoulas, Melita D. Irving, Ana Beleza-Meireles, Fernando Rivadeneira, Emma Duncan, J. Brent Richards, David J. Adams, Christopher J. Lelliott, Robert Brink, Tri Giang Phan, John A. Eisman, David M. Evans, Eleftheria Zeggini, Paul A. Baldock, J. H.Duncan Bassett, Graham R. Williams, Peter I. Croucher^*

^*Corresponding author for this work

Internal Medicine

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

56 Citations (Scopus)

Abstract

Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10⁻²²) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10⁻¹³) and osteoarthritis (P = 1.6 × 10⁻⁷). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease.

Original language	English
Article number	2444
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-22517-1
Publication status	Published - 5 May 2021

Bibliographical note

Funding Information:
This work was supported by a Wellcome Trust Strategic Award (101123/Z/13/A) to G.R. W, P.I.C. and J.H.D.B, and by Mrs Janice Gibson and the Ernest Heine Family Foundation. P.I.C is supported by Mrs Janice Gibson and the Ernest Heine Family Foundation. J.H.D.B and G.R.W received a Wellcome Trust Joint Investigator Award (110141/Z/ 15/Z and 110140/Z/15/Z) and EU H2020 THYRAGE Grant (666869). S.E.Y and A.P.C were funded by the Australian Government Research Training Program Scholarships. J. P.K was funded by a University of Queensland Development Fellowship (UQFEL1718945), a National Health and Medical Research Council (Australia) Investigator grant (GNT1177938) and project grant (GNT1158758). J.T.S was funded by a University International Postgraduate Award Scholarship (UNSW). J.A.M was funded by a Banting Postdoctoral Fellowship. J.M.W.Q was funded by an Australian National Health and Medical Research Council project grant (ID: GNT1057706). M.J was funded by Viapath. J.B.R was supported by the Canadian Institutes of Health Research (CIHR), the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation for Innovation, the NIH Foundation, Cancer Research UK and the Fonds de Recherche Québec Santé (FRQS). J.B.R. is supported by a FRQS Clinical Research Scholarship. TwinsUK is funded by the Welcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. D.J.A and C.J.L were funded by Wellcome Trust Strategic Awards. D.M.E. was funded by an Australian National Health and Medical Research Council Senior Research Fellowship (APP1137714). T.G.P was funded by an Australian National Health and Medical Research Council Senior Research Fellowship (1155678). This research has been conducted using the UK Biobank Resource (accession IDs: 12703). This work was assisted by phenotyping expertise provided by Anne-Tounsia Adoum, Justyna Miszkiewicz, Rebecca Allen, Jayashree Bagchi Chakraborty, Katharine F Curry, Hannah F. Dewhurst, Apos-tolos Gogakos, Naila Mannan, Hayley J Protheroe, Penny C Sparkes, Valerie Vancollie and Fiona Kussy. Ya Xiao assisted with animal studies. The Sanger Institute’s Research Support Facility, Mouse Pipelines and Mouse Informatics Group generated mice and collected materials for this manuscript. This research has been conducted using the UK Biobank Resource (accession ID: 53641).

Publisher Copyright:
© 2021, The Author(s).

UN SDGs

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

Access to Document

10.1038/s41467-021-22517-1

Cite this

Youlten, S. E., Kemp, J. P., Logan, J. G., Ghirardello, E. J., Sergio, C. M., Dack, M. R. G., Guilfoyle, S. E., Leitch, V. D., Butterfield, N. C., Komla-Ebri, D., Chai, R. C., Corr, A. P., Smith, J. T., Mohanty, S. T., Morris, J. A., McDonald, M. M., Quinn, J. M. W., McGlade, A. R., Bartonicek, N., ... Croucher, P. I. (2021). Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease. Nature Communications, 12(1), Article 2444. https://doi.org/10.1038/s41467-021-22517-1

@article{f586a47b51a64d98bdb236b67789ec89,

title = "Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease",

abstract = "Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10−22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10−13) and osteoarthritis (P = 1.6 × 10−7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease.",

author = "Youlten, {Scott E.} and Kemp, {John P.} and Logan, {John G.} and Ghirardello, {Elena J.} and Sergio, {Claudio M.} and Dack, {Michael R.G.} and Guilfoyle, {Siobhan E.} and Leitch, {Victoria D.} and Butterfield, {Natalie C.} and Davide Komla-Ebri and Chai, {Ryan C.} and Corr, {Alexander P.} and Smith, {James T.} and Mohanty, {Sindhu T.} and Morris, {John A.} and McDonald, {Michelle M.} and Quinn, {Julian M.W.} and McGlade, {Amelia R.} and Nenad Bartonicek and Matt Jansson and Konstantinos Hatzikotoulas and Irving, {Melita D.} and Ana Beleza-Meireles and Fernando Rivadeneira and Emma Duncan and Richards, {J. Brent} and Adams, {David J.} and Lelliott, {Christopher J.} and Robert Brink and Phan, {Tri Giang} and Eisman, {John A.} and Evans, {David M.} and Eleftheria Zeggini and Baldock, {Paul A.} and Bassett, {J. H.Duncan} and Williams, {Graham R.} and Croucher, {Peter I.}",

note = "Funding Information: This work was supported by a Wellcome Trust Strategic Award (101123/Z/13/A) to G.R. W, P.I.C. and J.H.D.B, and by Mrs Janice Gibson and the Ernest Heine Family Foundation. P.I.C is supported by Mrs Janice Gibson and the Ernest Heine Family Foundation. J.H.D.B and G.R.W received a Wellcome Trust Joint Investigator Award (110141/Z/ 15/Z and 110140/Z/15/Z) and EU H2020 THYRAGE Grant (666869). S.E.Y and A.P.C were funded by the Australian Government Research Training Program Scholarships. J. P.K was funded by a University of Queensland Development Fellowship (UQFEL1718945), a National Health and Medical Research Council (Australia) Investigator grant (GNT1177938) and project grant (GNT1158758). J.T.S was funded by a University International Postgraduate Award Scholarship (UNSW). J.A.M was funded by a Banting Postdoctoral Fellowship. J.M.W.Q was funded by an Australian National Health and Medical Research Council project grant (ID: GNT1057706). M.J was funded by Viapath. J.B.R was supported by the Canadian Institutes of Health Research (CIHR), the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation for Innovation, the NIH Foundation, Cancer Research UK and the Fonds de Recherche Qu{\'e}bec Sant{\'e} (FRQS). J.B.R. is supported by a FRQS Clinical Research Scholarship. TwinsUK is funded by the Welcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust in partnership with King{\textquoteright}s College London. D.J.A and C.J.L were funded by Wellcome Trust Strategic Awards. D.M.E. was funded by an Australian National Health and Medical Research Council Senior Research Fellowship (APP1137714). T.G.P was funded by an Australian National Health and Medical Research Council Senior Research Fellowship (1155678). This research has been conducted using the UK Biobank Resource (accession IDs: 12703). This work was assisted by phenotyping expertise provided by Anne-Tounsia Adoum, Justyna Miszkiewicz, Rebecca Allen, Jayashree Bagchi Chakraborty, Katharine F Curry, Hannah F. Dewhurst, Apos-tolos Gogakos, Naila Mannan, Hayley J Protheroe, Penny C Sparkes, Valerie Vancollie and Fiona Kussy. Ya Xiao assisted with animal studies. The Sanger Institute{\textquoteright}s Research Support Facility, Mouse Pipelines and Mouse Informatics Group generated mice and collected materials for this manuscript. This research has been conducted using the UK Biobank Resource (accession ID: 53641). Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = may,

day = "5",

doi = "10.1038/s41467-021-22517-1",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Youlten, SE, Kemp, JP, Logan, JG, Ghirardello, EJ, Sergio, CM, Dack, MRG, Guilfoyle, SE, Leitch, VD, Butterfield, NC, Komla-Ebri, D, Chai, RC, Corr, AP, Smith, JT, Mohanty, ST, Morris, JA, McDonald, MM, Quinn, JMW, McGlade, AR, Bartonicek, N, Jansson, M, Hatzikotoulas, K, Irving, MD, Beleza-Meireles, A, Rivadeneira, F, Duncan, E, Richards, JB, Adams, DJ, Lelliott, CJ, Brink, R, Phan, TG, Eisman, JA, Evans, DM, Zeggini, E, Baldock, PA, Bassett, JHD, Williams, GR & Croucher, PI 2021, 'Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease', Nature Communications, vol. 12, no. 1, 2444. https://doi.org/10.1038/s41467-021-22517-1

TY - JOUR

T1 - Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease

AU - Youlten, Scott E.

AU - Kemp, John P.

AU - Logan, John G.

AU - Ghirardello, Elena J.

AU - Sergio, Claudio M.

AU - Dack, Michael R.G.

AU - Guilfoyle, Siobhan E.

AU - Leitch, Victoria D.

AU - Butterfield, Natalie C.

AU - Komla-Ebri, Davide

AU - Chai, Ryan C.

AU - Corr, Alexander P.

AU - Smith, James T.

AU - Mohanty, Sindhu T.

AU - Morris, John A.

AU - McDonald, Michelle M.

AU - Quinn, Julian M.W.

AU - McGlade, Amelia R.

AU - Bartonicek, Nenad

AU - Jansson, Matt

AU - Hatzikotoulas, Konstantinos

AU - Irving, Melita D.

AU - Beleza-Meireles, Ana

AU - Rivadeneira, Fernando

AU - Duncan, Emma

AU - Richards, J. Brent

AU - Adams, David J.

AU - Lelliott, Christopher J.

AU - Brink, Robert

AU - Phan, Tri Giang

AU - Eisman, John A.

AU - Evans, David M.

AU - Zeggini, Eleftheria

AU - Baldock, Paul A.

AU - Bassett, J. H.Duncan

AU - Williams, Graham R.

AU - Croucher, Peter I.

N1 - Funding Information: This work was supported by a Wellcome Trust Strategic Award (101123/Z/13/A) to G.R. W, P.I.C. and J.H.D.B, and by Mrs Janice Gibson and the Ernest Heine Family Foundation. P.I.C is supported by Mrs Janice Gibson and the Ernest Heine Family Foundation. J.H.D.B and G.R.W received a Wellcome Trust Joint Investigator Award (110141/Z/ 15/Z and 110140/Z/15/Z) and EU H2020 THYRAGE Grant (666869). S.E.Y and A.P.C were funded by the Australian Government Research Training Program Scholarships. J. P.K was funded by a University of Queensland Development Fellowship (UQFEL1718945), a National Health and Medical Research Council (Australia) Investigator grant (GNT1177938) and project grant (GNT1158758). J.T.S was funded by a University International Postgraduate Award Scholarship (UNSW). J.A.M was funded by a Banting Postdoctoral Fellowship. J.M.W.Q was funded by an Australian National Health and Medical Research Council project grant (ID: GNT1057706). M.J was funded by Viapath. J.B.R was supported by the Canadian Institutes of Health Research (CIHR), the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation for Innovation, the NIH Foundation, Cancer Research UK and the Fonds de Recherche Québec Santé (FRQS). J.B.R. is supported by a FRQS Clinical Research Scholarship. TwinsUK is funded by the Welcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. D.J.A and C.J.L were funded by Wellcome Trust Strategic Awards. D.M.E. was funded by an Australian National Health and Medical Research Council Senior Research Fellowship (APP1137714). T.G.P was funded by an Australian National Health and Medical Research Council Senior Research Fellowship (1155678). This research has been conducted using the UK Biobank Resource (accession IDs: 12703). This work was assisted by phenotyping expertise provided by Anne-Tounsia Adoum, Justyna Miszkiewicz, Rebecca Allen, Jayashree Bagchi Chakraborty, Katharine F Curry, Hannah F. Dewhurst, Apos-tolos Gogakos, Naila Mannan, Hayley J Protheroe, Penny C Sparkes, Valerie Vancollie and Fiona Kussy. Ya Xiao assisted with animal studies. The Sanger Institute’s Research Support Facility, Mouse Pipelines and Mouse Informatics Group generated mice and collected materials for this manuscript. This research has been conducted using the UK Biobank Resource (accession ID: 53641). Publisher Copyright: © 2021, The Author(s).

PY - 2021/5/5

Y1 - 2021/5/5

N2 - Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10−22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10−13) and osteoarthritis (P = 1.6 × 10−7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease.

AB - Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10−22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10−13) and osteoarthritis (P = 1.6 × 10−7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease.

UR - http://www.scopus.com/inward/record.url?scp=85105379914&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-22517-1

DO - 10.1038/s41467-021-22517-1

M3 - Article

C2 - 33953184

AN - SCOPUS:85105379914

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2444

ER -

Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease

Abstract

Bibliographical note

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this