Disparate bone anabolic cues activate bone formation by regulating the rapid lysosomal degradation of sclerostin protein
- University of Maryland, School of Medicine, United States
- Myologica, LLC, United States
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
Katrina M Williams
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
© 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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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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