1. Cell Biology

Disparate bone anabolic cues activate bone formation by regulating the rapid lysosomal degradation of sclerostin protein

  1. Nicole R Gould  Is a corresponding author
  2. Katrina M Williams
  3. Humberto C Joca
  4. Olivia M Torre
  5. James S Lyons
  6. Jenna M Leser
  7. Manasa P Srikanth
  8. Marcus Hughes
  9. Ramzi J Khairallah
  10. Ricardo A Feldman Dr.
  11. Christopher W Ward  Is a corresponding author
  12. Joseph P Stains  Is a corresponding author
  1. University of Maryland, School of Medicine, United States
  2. Myologica, LLC, United States
https://doi.org/10.7554/eLife.64393
Share this article
Cite this article
  1. Nicole R Gould
  2. Katrina M Williams
  3. Humberto C Joca
  4. Olivia M Torre
  5. James S Lyons
  6. Jenna M Leser
  7. Manasa P Srikanth
  8. Marcus Hughes
  9. Ramzi J Khairallah
  10. Ricardo A Feldman Dr.
  11. Christopher W Ward
  12. Joseph P Stains
(2021)
Disparate bone anabolic cues activate bone formation by regulating the rapid lysosomal degradation of sclerostin protein
eLife 10:e64393.
https://doi.org/10.7554/eLife.64393
  2. Download BibTeX
  3. Download .RIS

Abstract

The down regulation of sclerostin in osteocytes mediates bone formation in response to mechanical cues and parathyroid hormone (PTH). To date, the regulation of sclerostin has been attributed exclusively to the transcriptional downregulation of the Sost gene hours after stimulation. Using mouse models and rodent cell lines, we describe the rapid, minutes-scale post-translational degradation of sclerostin protein by the lysosome following mechanical load and PTH. We present a model, integrating both new and established mechanically- and hormonally-activated effectors into the regulated degradation of sclerostin by lysosomes. Using a mouse forelimb mechanical loading model, we find transient inhibition of lysosomal degradation or the upstream mechano-signaling pathway controlling sclerostin abundance impairs subsequent load-induced bone formation by preventing sclerostin degradation. We also link dysfunctional lysosomes to aberrant sclerostin regulation using human Gaucher disease iPSCs. These results reveal how bone anabolic cues post-translationally regulate sclerostin abundance in osteocytes to regulate bone formation.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Nicole R Gould

    Orthopaedics, University of Maryland, School of Medicine, Baltimore, United States
    For correspondence
    ngould@som.umaryland.edu
    Competing interests
    No competing interests declared.

  2. Katrina M Williams

    Orthopaedics, University of Maryland, School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3729-0630

  3. Humberto C Joca

    Center for Biomedical Engineering & Technology, University of Maryland, School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.

  4. Olivia M Torre

    Orthopaedics, University of Maryland, School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3405-6259

  5. James S Lyons

    Orthopaedics, University of Maryland, School of Medicine, Baltimore, United States
    Competing interests
    James S Lyons, Holds two patents related to this work. One for the custom fluid shear device used for these experiments (US Patent No US 2017/0276666 A1) and a second for the targeting microtubules (part of this mechano-transduction pathway) to improve bone mass (US Patent No US 2019/0351055 A1)..

  6. Jenna M Leser

    Orthopaedics, University of Maryland, School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.

  7. Manasa P Srikanth

    Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.

  8. Marcus Hughes

    Orthopaedics, University of Maryland, School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.

  9. Ramzi J Khairallah

    N/A, Myologica, LLC, New Market, United States
    Competing interests
    Ramzi J Khairallah, Has a patent pending on colchicine analogs to treat musculoskeletal disorders (PCT/US2018/038300).Ramzi J. Khairallah is affiliated with Myologica, LLC. The author has no financial interests to declare..

  10. Ricardo A Feldman Dr.

    Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.

  11. Christopher W Ward

    Orthopaedics, University of Maryland, School of Medicine, Baltimore, United States
    For correspondence
    ward@som.umaryland.edu
    Competing interests
    Christopher W Ward, Holds two patents related to this work. One for the custom fluid shear device used for these experiments (US Patent No US 2017/0276666 A1) and a second for the targeting microtubules (part of this mechano-transduction pathway) to improve bone mass (US Patent No US 2019/0351055 A1). Another patent pending on colchicine analogs to treat musculoskeletal disorders (PCT/US2018/038300)..

  12. Joseph P Stains

    Orthopaedics, University of Maryland, School of Medicine, Baltimore, United States
    For correspondence
    jstains@som.umaryland.edu
    Competing interests
    Joseph P Stains, Holds two patents related to this work. One for the custom fluid shear device used for these experiments (US Patent No US 2017/0276666 A1) and a second for the targeting microtubules (part of this mechano-transduction pathway) to improve bone mass (US Patent No US 2019/0351055 A1)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1610-4694

Funding

National Institutes of Health (AR071614)

  • Christopher W Ward
  • Joseph P Stains

Maryland Stem Cell Research Fund (2018-MSCRFD-4246)

  • Ricardo A Feldman Dr.

American Heart Association (19POST34450156)

  • Humberto C Joca

National Institutes of Health (AR071618,HL142290)

  • Christopher W Ward

National Institutes of Health (GM008181)

  • Nicole R Gould
  • James S Lyons

National Institutes of Health (AR007592)

  • Katrina M Williams

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

Reviewing Editor

  1. Subburaman Mohan, Loma Linda University, United States

Ethics

Animal experimentation: All of the animals were handled according to protocol approved by the Animal care and Use Committee at the University of Maryland School of Medicine (Protocol Numbers, 0617013 and 0520007).

Version history

  1. Received: October 27, 2020
  2. Accepted: March 26, 2021
  3. Accepted Manuscript published: March 29, 2021 (version 1)
  4. Version of Record published: April 8, 2021 (version 2)
  5. Version of Record updated: April 27, 2021 (version 3)

Copyright

© 2021, Gould 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

  • 2,231
    Page views
  • 320
    Downloads
  • 17
    Citations

Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, Scopus.

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. Nicole R Gould
  2. Katrina M Williams
  3. Humberto C Joca
  4. Olivia M Torre
  5. James S Lyons
  6. Jenna M Leser
  7. Manasa P Srikanth
  8. Marcus Hughes
  9. Ramzi J Khairallah
  10. Ricardo A Feldman Dr.
  11. Christopher W Ward
  12. Joseph P Stains
(2021)
Disparate bone anabolic cues activate bone formation by regulating the rapid lysosomal degradation of sclerostin protein
eLife 10:e64393.
https://doi.org/10.7554/eLife.64393

Share this article

https://doi.org/10.7554/eLife.64393

Categories and tags

Research organism

Further reading

    1. Cell Biology
    2. Chromosomes and Gene Expression

    Heat stress impairs centromere structure and segregation of meiotic chromosomes in Arabidopsis

    Lucie Crhak Khaitova, Pavlina Mikulkova ... Karel Riha
    Research Article

    Heat stress is a major threat to global crop production, and understanding its impact on plant fertility is crucial for developing climate-resilient crops. Despite the known negative effects of heat stress on plant reproduction, the underlying molecular mechanisms remain poorly understood. Here, we investigated the impact of elevated temperature on centromere structure and chromosome segregation during meiosis in Arabidopsis thaliana. Consistent with previous studies, heat stress leads to a decline in fertility and micronuclei formation in pollen mother cells. Our results reveal that elevated temperature causes a decrease in the amount of centromeric histone and the kinetochore protein BMF1 at meiotic centromeres with increasing temperature. Furthermore, we show that heat stress increases the duration of meiotic divisions and prolongs the activity of the spindle assembly checkpoint during meiosis I, indicating an impaired efficiency of the kinetochore attachments to spindle microtubules. Our analysis of mutants with reduced levels of centromeric histone suggests that weakened centromeres sensitize plants to elevated temperature, resulting in meiotic defects and reduced fertility even at moderate temperatures. These results indicate that the structure and functionality of meiotic centromeres in Arabidopsis are highly sensitive to heat stress, and suggest that centromeres and kinetochores may represent a critical bottleneck in plant adaptation to increasing temperatures.

    1. Cell Biology

    High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen

    Wan-ping Yang, Mei-qi Li ... Qian-qian Luo
    Research Article

    High-altitude polycythemia (HAPC) affects individuals living at high altitudes, characterized by increased red blood cells (RBCs) production in response to hypoxic conditions. The exact mechanisms behind HAPC are not fully understood. We utilized a mouse model exposed to hypobaric hypoxia (HH), replicating the environmental conditions experienced at 6000 m above sea level, coupled with in vitro analysis of primary splenic macrophages under 1% O2 to investigate these mechanisms. Our findings indicate that HH significantly boosts erythropoiesis, leading to erythrocytosis and splenic changes, including initial contraction to splenomegaly over 14 days. A notable decrease in red pulp macrophages (RPMs) in the spleen, essential for RBCs processing, was observed, correlating with increased iron release and signs of ferroptosis. Prolonged exposure to hypoxia further exacerbated these effects, mirrored in human peripheral blood mononuclear cells. Single-cell sequencing showed a marked reduction in macrophage populations, affecting the spleen’s ability to clear RBCs and contributing to splenomegaly. Our findings suggest splenic ferroptosis contributes to decreased RPMs, affecting erythrophagocytosis and potentially fostering continuous RBCs production in HAPC. These insights could guide the development of targeted therapies for HAPC, emphasizing the importance of splenic macrophages in disease pathology.

    1. Cell Biology

    Golgi Apparatus: Making progress

    Jurgen Denecke
    Insight

    Mapping proteins in and associated with the Golgi apparatus reveals how this cellular compartment emerges in budding yeast and progresses over time.