Osteocytes regulate senescence of bone and bone marrow

  1. Peng Ding
  2. Chuan Gao
  3. Youshui Gao
  4. Delin Liu
  5. Hao Li
  6. Jun Xu
  7. Xiaoyi Chen
  8. Yigang Huang
  9. Changqing Zhang  Is a corresponding author
  10. Ming Hao Zheng  Is a corresponding author
  11. Junjie Gao  Is a corresponding author
  1. Shanghai Sixth People's Hospital, China
  2. University of Western Australia, Australia
  3. University of Chinese Academy of Sciences, China

Abstract

The skeletal system contains a series of sophisticated cellular lineages arisen from the mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), that determine the homeostasis of bone and bone marrow. Here we reasoned that osteocyte may exert a function in regulation of these lineage cell specifications and tissue homeostasis. Using a mouse model of conditional deletion of osteocytes by the expression of diphtheria toxin subunit 𝛼 (DTA) in dentin matrix protein 1 (DMP1) positive osteocytes, we demonstrated that partial ablation of DMP1 positive osteocytes caused severe sarcopenia, osteoporosis and degenerative kyphosis, leading to shorter lifespan in these animals. Osteocytes reduction altered mesenchymal lineage commitment resulting in impairment of osteogenesis and induction of osteoclastogensis. Single cell RNA sequencing further revealed that hematopoietic lineage was mobilized towards myeloid lineage differentiation with expanded myeloid progenitors, neutrophils and monocytes, while the lymphopoiesis was impaired with reduced B cells in the osteocyte ablation mice. The acquisition of a senescence-associated secretory phenotype (SASP) in both osteoprogenic and myeloid lineage cells was the underlying cause. Together, we showed that osteocytes play critical roles in regulation of lineage cell specifications in bone and bone marrow through mediation of senescence.

Data availability

ScRNA-Seq and RNA-seq data have been deposited into GEO repository with accession codes GSE202516 and GSE202356 respectively. Source data have been deposited in Dryad.

The following data sets were generated

Article and author information

Author details

  1. Peng Ding

    Department of Orthopaedics, Shanghai Sixth People's Hospital, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9348-8134
  2. Chuan Gao

    Department of Orthopaedics, Shanghai Sixth People's Hospital, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Youshui Gao

    Department of Orthopaedics, Shanghai Sixth People's Hospital, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Delin Liu

    Centre for Orthopaedic Translational Research, University of Western Australia, Perth, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Hao Li

    Department of Orthopaedics, Shanghai Sixth People's Hospital, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Jun Xu

    Department of Orthopaedics, Shanghai Sixth People's Hospital, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Xiaoyi Chen

    Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Yigang Huang

    Department of Orthopaedics, Shanghai Sixth People's Hospital, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Changqing Zhang

    Department of Orthopaedics, Shanghai Sixth People's Hospital, Shanghai, China
    For correspondence
    zhangcq@sjtu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  10. Ming Hao Zheng

    Centre for Orthopaedic Translational Research, University of Western Australia, Nedlands, Australia
    For correspondence
    minghao.zheng@uwa.edu.au
    Competing interests
    The authors declare that no competing interests exist.
  11. Junjie Gao

    Department of Orthopaedics, Shanghai Sixth People's Hospital, Shanghai, China
    For correspondence
    colingjj@163.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4820-8524

Funding

National Natural Science Foundation of China (82002339)

  • Junjie Gao

National Natural Science Foundation of China (81820108020)

  • Changqing Zhang

Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal System (BJ1-9000-22-4002)

  • Changqing Zhang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Mei Wan, Johns Hopkins University, United States

Ethics

Animal experimentation: All mice experiments were approved by the Animal Care and Use Committee of Shanghai Sixth People's Hospital (Permit number: 2021-0935, 2021-0936). All surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering.

Version history

  1. Received: June 29, 2022
  2. Preprint posted: July 18, 2022 (view preprint)
  3. Accepted: October 27, 2022
  4. Accepted Manuscript published: October 28, 2022 (version 1)
  5. Version of Record published: November 21, 2022 (version 2)

Copyright

© 2022, Ding et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Peng Ding
  2. Chuan Gao
  3. Youshui Gao
  4. Delin Liu
  5. Hao Li
  6. Jun Xu
  7. Xiaoyi Chen
  8. Yigang Huang
  9. Changqing Zhang
  10. Ming Hao Zheng
  11. Junjie Gao
(2022)
Osteocytes regulate senescence of bone and bone marrow
eLife 11:e81480.
https://doi.org/10.7554/eLife.81480

Share this article

https://doi.org/10.7554/eLife.81480

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