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

Author

Listed:
  • Scott E. Youlten

    (Bone Biology, Garvan Institute of Medical Research
    St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney)

  • John P. Kemp

    (University of Queensland Diamantina Institute, UQ
    University of Bristol)

  • John G. Logan

    (Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London)

  • Elena J. Ghirardello

    (Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London)

  • Claudio M. Sergio

    (Bone Biology, Garvan Institute of Medical Research)

  • Michael R. G. Dack

    (Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London)

  • Siobhan E. Guilfoyle

    (Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London)

  • Victoria D. Leitch

    (Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London
    RMIT University)

  • Natalie C. Butterfield

    (Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London)

  • Davide Komla-Ebri

    (Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London)

  • Ryan C. Chai

    (Bone Biology, Garvan Institute of Medical Research)

  • Alexander P. Corr

    (Bone Biology, Garvan Institute of Medical Research
    St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney
    University of Bath)

  • James T. Smith

    (Bone Biology, Garvan Institute of Medical Research
    St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney
    University of Bath)

  • Sindhu T. Mohanty

    (Bone Biology, Garvan Institute of Medical Research)

  • John A. Morris

    (New York Genome Center
    New York University)

  • Michelle M. McDonald

    (Bone Biology, Garvan Institute of Medical Research
    St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney)

  • Julian M. W. Quinn

    (Bone Biology, Garvan Institute of Medical Research)

  • Amelia R. McGlade

    (Bone Biology, Garvan Institute of Medical Research)

  • Nenad Bartonicek

    (Garvan Institute of Medical Research and The Kinghorn Cancer Centre)

  • Matt Jansson

    (Viapath Genetics Laboratory, Viapath Analytics LLP, Guy’s Hospital
    Department of Clinical Genetics, Guy’s Hospital)

  • Konstantinos Hatzikotoulas

    (Institute of Translational Genomics, Helmholtz Zentrum München – German Research Center for Environmental Health
    Wellcome Sanger Institute, Wellcome Genome Campus)

  • Melita D. Irving

    (Department of Clinical Genetics, Guy’s and St Thomas’ NHS Trust)

  • Ana Beleza-Meireles

    (University Hospitals Bristol)

  • Fernando Rivadeneira

    (Department of Internal Medicine, Erasmus, MC)

  • Emma Duncan

    (Faculty of Life Sciences and Medicine, Department of Twin Research & Genetic Epidemiology, School of Life Course Sciences, King’s College London
    Queensland University of Technology
    University of Queensland)

  • J. Brent Richards

    (Faculty of Life Sciences and Medicine, Department of Twin Research & Genetic Epidemiology, School of Life Course Sciences, King’s College London
    McGill University)

  • David J. Adams

    (Wellcome Sanger Institute)

  • Christopher J. Lelliott

    (Wellcome Sanger Institute)

  • Robert Brink

    (St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney
    Division of Immunology, Garvan Institute of Medical Research)

  • Tri Giang Phan

    (St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney
    Division of Immunology, Garvan Institute of Medical Research)

  • John A. Eisman

    (Bone Biology, Garvan Institute of Medical Research
    St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney
    University of Notre Dame Australia)

  • David M. Evans

    (University of Queensland Diamantina Institute, UQ
    University of Bristol)

  • Eleftheria Zeggini

    (Institute of Translational Genomics, Helmholtz Zentrum München – German Research Center for Environmental Health
    Wellcome Sanger Institute, Wellcome Genome Campus)

  • Paul A. Baldock

    (Bone Biology, Garvan Institute of Medical Research)

  • J. H. Duncan Bassett

    (Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London)

  • Graham R. Williams

    (Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London)

  • Peter I. Croucher

    (Bone Biology, Garvan Institute of Medical Research
    St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney
    School of Biotechnology and Biomolecular Sciences, UNSW Australia)

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.

Suggested Citation

  • 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, 2021. "Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease," Nature Communications, Nature, vol. 12(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22517-1
    DOI: 10.1038/s41467-021-22517-1
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    Cited by:

    1. Jialiang S. Wang & Tushar Kamath & Courtney M. Mazur & Fatemeh Mirzamohammadi & Daniel Rotter & Hironori Hojo & Christian D. Castro & Nicha Tokavanich & Rushi Patel & Nicolas Govea & Tetsuya Enishi & , 2021. "Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    2. Yongkuk Park & Tadatoshi Sato & Jungwoo Lee, 2023. "Functional and analytical recapitulation of osteoclast biology on demineralized bone paper," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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