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

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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.

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

Article and author information

Author details

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.
Katrina M Williams

Orthopaedics, University of Maryland, School of Medicine, Baltimore, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-3729-0630
Humberto C Joca

Center for Biomedical Engineering & Technology, University of Maryland, School of Medicine, Baltimore, United States

Competing interests
No competing interests declared.
Olivia M Torre

Orthopaedics, University of Maryland, School of Medicine, Baltimore, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-3405-6259
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)..
Jenna M Leser

Orthopaedics, University of Maryland, School of Medicine, Baltimore, United States

Competing interests
No competing interests declared.
Manasa P Srikanth

Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, United States

Competing interests
No competing interests declared.
Marcus Hughes

Orthopaedics, University of Maryland, School of Medicine, Baltimore, United States

Competing interests
No competing interests declared.
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..
Ricardo A Feldman Dr.

Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, United States

Competing interests
No competing interests declared.
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)..
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)..

"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).

Copyright

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.