Impaired bone strength and bone microstructure in a novel early-onset osteoporotic rat model with a clinically relevant PLS3 mutation

  1. Jing Hu
  2. Bingna Zhou
  3. Xiaoyun Lin
  4. Qian Zhang
  5. Feifei Guan
  6. Lei Sun
  7. Jiayi Liu
  8. Ou Wang
  9. Yan Jiang
  10. Wei-bo Xia
  11. Xiaoping Xing
  12. Mei Li  Is a corresponding author
  1. Peking Union Medical College Hospital, China
  2. Peking Union Medical College, China

Abstract

Plastin 3 (PLS3), a protein involved in formation of filamentous actin (F-actin) bundles, is important in human bone health. Recent studies identify PLS3 as a novel bone regulator and PLS3 mutations can lead to a rare monogenic early-onset osteoporosis. However, the mechanism of PLS3 mutation leading to osteoporosis is unknown, and its effective treatment strategies have not been established. Here we have constructed a novel rat model with clinically relevant hemizygous E10-16del mutation in PLS3 (PLS3E10-16del/0) that recapitulates the osteoporotic phenotypes with obviously thinner cortical thickness, significant decreases in yield load, maximum load, and breaking load of femora at 3, 6, 9 months old compared to wild type rats. Histomorphometric analysis indicates a significantly lower mineral apposition rate in PLS3E10-16del/0 rats. Treatment with alendronate (1.0 ug/kg per day) or teriparatide (40ug/kg five times weekly) for 8 weeks significantly improves bone mass and bone microarchitecture, and bone strength is significantly increased after teriparatide treatment (P<0.05). Thus, our results indicate that PLS3 plays an important role in the regulation of bone microstructure and bone strength, and we provide a novel animal model for the study of X-linked early-onset osteoporosis. Alendronate and teriparatide treatment could be a potential treatment for early-onset osteoporosis induced by PLS3 mutation.

Data availability

All data analyzed during this study are included in the manuscript and supporting file. Source Data files have been provided for Figures 1-4.

Article and author information

Author details

  1. Jing Hu

    Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Bingna Zhou

    Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Xiaoyun Lin

    Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Qian Zhang

    Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Feifei Guan

    Institute of Laboratory Animal Science, Peking Union Medical College, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Lei Sun

    Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Jiayi Liu

    Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Ou Wang

    Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Yan Jiang

    Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Wei-bo Xia

    Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Xiaoping Xing

    Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Mei Li

    Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China
    For correspondence
    limeilzh@sina.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4380-3511

Funding

National Key Research and Development Program of China (2018YFA0800801,2021YFC2501704)

  • Mei Li

Chinese Academy of Medical Sciences Initiative for Innovative Medicine (2021-I2M-C&T-B-007,2021-I2M-1-051)

  • Mei Li

National Natural Science Foundation of China (No.81873668,82070908)

  • Mei Li

Beijing Natural Science Foundation (7202153)

  • Mei Li

Fundamental Research Funds for the Central Universities (3332022102)

  • Jing Hu

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

Reviewing Editor

  1. Mishaela R Rubin, Columbia University Medical Center, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animal experiments were approved by the Institutional Animal Care and Use Committee of the Peking Union Medical College Hospital (XHDW-2021-027). Every effort was made to minimize pain and suffering by providing support when necessary and choosing ethical endpoints.

Version history

  1. Received: May 18, 2022
  2. Preprint posted: July 2, 2022 (view preprint)
  3. Accepted: April 20, 2023
  4. Accepted Manuscript published: April 21, 2023 (version 1)
  5. Version of Record published: May 4, 2023 (version 2)

Copyright

© 2023, Hu 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. Jing Hu
  2. Bingna Zhou
  3. Xiaoyun Lin
  4. Qian Zhang
  5. Feifei Guan
  6. Lei Sun
  7. Jiayi Liu
  8. Ou Wang
  9. Yan Jiang
  10. Wei-bo Xia
  11. Xiaoping Xing
  12. Mei Li
(2023)
Impaired bone strength and bone microstructure in a novel early-onset osteoporotic rat model with a clinically relevant PLS3 mutation
eLife 12:e80365.
https://doi.org/10.7554/eLife.80365

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https://doi.org/10.7554/eLife.80365

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