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

Lindsey H. Remark; Kevin Leclerc; Malissa Ramsukh; Ziyan Lin; Sooyeon Lee; Backialakshmi Dharmalingam; Lauren Gillinov; Vasudev V. Nayak; Paulo El Parente; Margaux Sambon; Pablo J. Atria; Mohamed A.E. Ali; Lukasz Witek; Alesha B. Castillo; Christopher Y, Park; Ralf H. Adams; Aristotelis Tsirigos; Sophie M. Morgani; Philipp Leucht

doi:10.1038/s41413-023-00283-8

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

Lindsey H. Remark, Kevin Leclerc, Malissa Ramsukh, Ziyan Lin, Sooyeon Lee, Backialakshmi Dharmalingam, Lauren Gillinov, Vasudev V. Nayak, Paulo El Parente, Margaux Sambon, Pablo J. Atria, Mohamed A.E. Ali, Lukasz Witek, Alesha B. Castillo, Christopher Y, Park, Ralf H. Adams, Aristotelis Tsirigos, Sophie M. Morgani, Philipp Leucht^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English
Article number	50
Journal	Bone Research
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41413-023-00283-8
State	Published - Dec 2023
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2023, West China School of Stomatology Sichuan University.

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Remark, L. H., Leclerc, K., Ramsukh, M., Lin, Z., Lee, S., Dharmalingam, B., Gillinov, L., Nayak, V. V., El Parente, P., Sambon, M., Atria, P. J., Ali, M. A. E., Witek, L., Castillo, A. B., Park, C. Y., Adams, R. H., Tsirigos, A., Morgani, S. M., & Leucht, P. (2023). Loss of Notch signaling in skeletal stem cells enhances bone formation with aging. Bone Research, 11(1), Article 50. https://doi.org/10.1038/s41413-023-00283-8

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title = "Loss of Notch signaling in skeletal stem cells enhances bone formation with aging",

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.",

author = "Remark, {Lindsey H.} and Kevin Leclerc and Malissa Ramsukh and Ziyan Lin and Sooyeon Lee and Backialakshmi Dharmalingam and Lauren Gillinov and Nayak, {Vasudev V.} and {El Parente}, Paulo and Margaux Sambon and Atria, {Pablo J.} and Ali, {Mohamed A.E.} and Lukasz Witek and Castillo, {Alesha B.} and Park, {Christopher Y,} and Adams, {Ralf H.} and Aristotelis Tsirigos and Morgani, {Sophie M.} and Philipp Leucht",

note = "Publisher Copyright: {\textcopyright} 2023, West China School of Stomatology Sichuan University.",

year = "2023",

month = dec,

doi = "10.1038/s41413-023-00283-8",

language = "English",

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Remark, LH, Leclerc, K, Ramsukh, M, Lin, Z, Lee, S, Dharmalingam, B, Gillinov, L, Nayak, VV, El Parente, P, Sambon, M, Atria, PJ, Ali, MAE, Witek, L, Castillo, AB, Park, CY, Adams, RH, Tsirigos, A, Morgani, SM & Leucht, P 2023, 'Loss of Notch signaling in skeletal stem cells enhances bone formation with aging', Bone Research, vol. 11, no. 1, 50. https://doi.org/10.1038/s41413-023-00283-8

TY - JOUR

T1 - Loss of Notch signaling in skeletal stem cells enhances bone formation with aging

AU - Remark, Lindsey H.

AU - Leclerc, Kevin

AU - Ramsukh, Malissa

AU - Lin, Ziyan

AU - Lee, Sooyeon

AU - Dharmalingam, Backialakshmi

AU - Gillinov, Lauren

AU - Nayak, Vasudev V.

AU - El Parente, Paulo

AU - Sambon, Margaux

AU - Atria, Pablo J.

AU - Ali, Mohamed A.E.

AU - Witek, Lukasz

AU - Castillo, Alesha B.

AU - Park, Christopher Y,

AU - Adams, Ralf H.

AU - Tsirigos, Aristotelis

AU - Morgani, Sophie M.

AU - Leucht, Philipp

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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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AN - SCOPUS:85172287737

SN - 2095-4700

VL - 11

JO - Bone Research

JF - Bone Research

IS - 1

M1 - 50

ER -

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

Abstract

Bibliographical note

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