Induction of osteogenesis by bone-targeted Notch activation
- Max Planck Institute for Molecular Biomedicine, Germany
- Guangzhou Institutes of Biomedicine and Health, China
Abstract
Declining bone mass is associated with aging and osteoporosis, a disease characterized by progressive weakening of the skeleton and increased fracture incidence. Growth and lifelong homeostasis of bone rely on interactions between different cell types including vascular cells and mesenchymal stromal cells (MSCs). As these interactions involve Notch signaling, we have explored whether treatment with secreted Notch ligand proteins can enhance osteogenesis in adult mice. We show that a bone-targeting, high affinity version of the ligand Delta-like 4, termed Dll4(E12), induces bone formation in male mice without causing adverse effects in other organs, which are known to rely on intact Notch signaling. Due to lower bone surface and thereby reduced retention of Dll4(E12), the same approach failed to promote osteogenesis in female and ovariectomized mice but strongly enhanced trabecular bone formation in combination with parathyroid hormone. Single cell analysis of stromal cells indicates that Dll4(E12) primarily acts on MSCs and has comparably minor effects on osteoblasts, endothelial cells or chondrocytes. We propose that activation of Notch signaling by bone-targeted fusion proteins might be therapeutically useful and can avoid detrimental effects in Notch-dependent processes in other organs.
Data availability
scRNA-seq data have been deposited in the GEO functional genomics data repository under the accession number GSE152285. Data can be accessed via https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE152285 with the token mzcbwwqgptidxmh.
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Induction of osteogenesis by bone-targeted Notch activationNCBI Gene Expression Omnibus, GSE152285.
Article and author information
Author details
Funding
Max Planck Society
- Ralf H Adams
European Research Council (AdG 339409 AngioBone)
- Ralf H Adams
European Research Council (AdG 786672 PROVEC)
- Ralf H Adams
Leducq Foundation
- Ralf H Adams
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Cheryl Ackert-Bicknell, University of Colorado, United States
Ethics
Animal experimentation: All animals were housed at the Max Planck Institute for Molecular Biomedicine and protocols were approved by animal ethics committees with permissions (Az 81-02.04.2019.A114 and Az 81-02.04.2020.A416) granted by the Landesamt für Natur, Umwelt und Verbraucherschutz (LANUV) of North Rhine-Westphalia. Every effort was made to minimize suffering.
Version history
- Received: June 18, 2020
- Accepted: February 3, 2022
- Accepted Manuscript published: February 4, 2022 (version 1)
- Version of Record published: February 25, 2022 (version 2)
Copyright
© 2022, Xu 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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Induction of osteogenesis by bone-targeted Notch activation
eLife 11:e60183.
https://doi.org/10.7554/eLife.60183
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