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Original Article | Open Access

Loss of Notch signaling in skeletal stem cells enhances bone formation with aging

Lindsey H. Remark1, Kevin Leclerc1, Malissa Ramsukh1, Ziyan Lin2, Sooyeon Lee1,3, Backialakshmi Dharmalingam4, Lauren Gillinov1, Vasudev V. Nayak5, Paulo El Parente1, Margaux Sambon1, Pablo J. Atria1, Mohamed A. E. Ali6, Lukasz Witek7,8,9, Alesha B. Castillo1, Christopher Y, Park6, Ralf H. Adams4, Aristotelis Tsirigos2, Sophie M. Morgani1, Philipp Leucht1,10( )
Department of Orthopaedic Surgery, NYU Robert I. Grossman School of Medicine, New York, NY, USA
Applied Bioinformatics Laboratories, NYU Grossman School of Medicine, New York, NY, USA
Institute of Comparative Molecular Endocrinology, Ulm University, Ulm, Germany
Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Münster, Faculty of Medicine, D-48149, Münster, Germany
Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
Department of Pathology, NYU Robert I. Grossman School of Medicine, New York, NY, USA
Biomaterials Division, New York University College of Dentistry, New York, NY, USA
Hansjörg Wyss Department of Plastic Surgery, NYU Grossman School of Medicine, New York University, New York, NY, USA
Department of Biomedical Engineering, Tandon School of Engineering, New York University, Brooklyn, NY, USA
Department of Cell Biology, NYU Robert I. Grossman School of Medicine, New York, NY, USA
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Abstract

Skeletal stem and progenitor cells (SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.

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Bone Research
Volume 11,
December 2023
Article number: 50
DOI: 10.1038/s41413-023-00283-8
Cite this article:
Remark LH, Leclerc K, Ramsukh M, et al. Loss of Notch signaling in skeletal stem cells enhances bone formation with aging. Bone Research, 2023, 11: 50. https://doi.org/10.1038/s41413-023-00283-8

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Received: 04 January 2023
Revised: 06 July 2023
Accepted: 19 July 2023
Published: 27 September 2023
© The Author(s) 2023

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