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

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.

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).

Reviewing Editor

  1. Subburaman Mohan, Loma Linda University, United States

Publication 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.

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  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

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