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.

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.

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.

Metrics

  • 455
    views
  • 91
    downloads
  • 4
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

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

Further reading

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics
    Omid Gholamalamdari, Tom van Schaik ... Andrew S Belmont
    Research Article

    Models of nuclear genome organization often propose a binary division into active versus inactive compartments yet typically overlook nuclear bodies. Here, we integrated analysis of sequencing and image-based data to compare genome organization in four human cell types relative to three different nuclear locales: the nuclear lamina, nuclear speckles, and nucleoli. Although gene expression correlates mostly with nuclear speckle proximity, DNA replication timing correlates with proximity to multiple nuclear locales. Speckle attachment regions emerge as DNA replication initiation zones whose replication timing and gene composition vary with their attachment frequency. Most facultative LADs retain a partially repressed state as iLADs, despite their positioning in the nuclear interior. Knock out of two lamina proteins, Lamin A and LBR, causes a shift of H3K9me3-enriched LADs from lamina to nucleolus, and a reciprocal relocation of H3K27me3-enriched partially repressed iLADs from nucleolus to lamina. Thus, these partially repressed iLADs appear to compete with LADs for nuclear lamina attachment with consequences for replication timing. The nuclear organization in adherent cells is polarized with nuclear bodies and genomic regions segregating both radially and relative to the equatorial plane. Together, our results underscore the importance of considering genome organization relative to nuclear locales for a more complete understanding of the spatial and functional organization of the human genome.

    1. Cell Biology
    2. Genetics and Genomics
    Keva Li, Nicholas Tolman ... UK Biobank Eye and Vision Consortium
    Research Article

    A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic-risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve = 0.579), they offered marginal prediction improvement in PRS-only-based models (p=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma PRS decile, with elevated glycolysis-related metabolites—lactate (p=8.8E-12), pyruvate (p=1.9E-10), and citrate (p=0.02)—linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (Pinteraction = 0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratiohighest vs. lowest total resilience metabolite quartile=0.71, 95% Confidence Interval = 0.64–0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (p=0.002) and optic nerve damage (p<0.0003) in Lmx1bV265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.