A Molecular Switch for Bone Loss

Blocking an abnormally active signaling pathway in skeletal stem and progenitor cells alleviates bone mass decline in middle-aged mice.

Black and white portrait by Mariella Bodemeier Loayza Careaga, PhD
| 4 min read
The image shows four different bones with varying degrees of osteoporosis.

Microcomputed tomography of mice femurs revealed that differences in bone mass and cell type emerge with age.

© iStock, CreVis2

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The human skeleton provides support, facilitates movement, and protects many internal organs in the body. However, as people age, their bones become weaker and more prone to fractures that take longer to heal. While these age-related changes are well known, the molecular mechanisms that mediate them remain poorly understood. In a study published in Bone Research, researchers reported that the Notch signaling pathway plays a key role in age-related bone degeneration in mice.1 They also identified a downstream mediator of this pathway that could be leveraged to mitigate bone weakening with aging.

There's a relative lack of understanding in the biology of how bones age.

-Charles Chan, Stanford University

“There's a relative lack of understanding in the biology of how bones age,” said Charles Chan, a developmental biologist at Stanford University who was not involved in the research. “This study is important because it looks at the types of cells that regenerate broken bones, the skeletal stem cells, and how they, in turn, are affected by aging.”

For the study, a team of researchers led by Philipp Leucht, an orthopedic surgeon and bone biology researcher at New York University, focused on skeletal stem and progenitor cells (SSPC), which are resident cells in the bone marrow that are key to bone development, maintenance, and repair.2 SSPC have the potential to become either bone-forming cells (osteoblasts) or fat-storing cells (adipocytes). As the skeletal tissue ages, these cells are more likely to become adipocytes, making bones more susceptible to fractures.3,4

See Also "Mechanical Force on the Skull May Aid Bone Regeneration"

To investigate the molecular mechanisms that determine SSPC fate with aging, the researchers collected hindlimb bones from young and middle-aged mice and analyzed the gene expression profiles of the skeletal tissue using single-cell RNA sequencing (scRNAseq). Consistent with previous studies, they found that as bones age, there is an upregulation of adipocyte-related genes and a downregulation of osteoblast-related genes in SSPC. The data also revealed an association between age-related bone degeneration and a significant upregulation of Notch signaling genes, suggesting that this pathway becomes abnormally active in SSPC as mice age.

Based on these findings, the team examined whether the Notch signaling pathway controls SSPC differentiation, making these cells more likely to become adipocytes with aging. To do so, they used genetically engineered mice in which the gene encoding the enzyme nicastrin was conditionally deleted. Nicastrin activates the Notch pathway by cleaving the Notch receptors, so deleting the coding gene prevented Notch signaling in these mice. “[This] mouse has just this amazing, intriguing phenotype of increasing bone mineral density with age—the opposite of what you usually see,” Leucht explained.

3D rendering of microcomputed tomography of mice femurs. The femur on the left is from a wildtype, middle-aged mouse. The femur on the right is from a Notch-deficient, middle-aged mouse.
Middle-aged mice with deficient Notch signaling showed increased bone mass compared to their middle-aged, wildtype counterparts.
Adapted from Remark et al., 2023, Bone Research (CC BY 4.0 DEED).


By looking at the transcriptional profile of the Notch-deficient mice, the team found upregulation of bone formation genes which might prime the SSPC for becoming osteoblasts. Microcomputed tomography of the femurs of middle-aged, Notch-deficient mice revealed an increase in bone mass and decrease in the number of adipocytes compared to their wildtype counterparts, indicating that loss of Notch signaling in SSPC prevents age-related bone degeneration. Chan pointed out that these findings are novel because the Notch signaling pathway has not been strongly implicated in how skeletal stem cells age.

Although these results suggest that modulating Notch signaling curbs age-related bone degeneration, Leucht explained that targeting this pathway is challenging because it interacts with many cellular pathways in different cell types. To uncover more specific and safer therapeutic targets, the researchers searched for molecules that carry Notch signaling forward in SSPC and analyzed their transcriptional profiles in the scRNAseq dataset. They identified the early B-cell factor 3 (Ebf3), a DNA-binding transcriptional factor, as a promising target because Ebf3 was expressed almost exclusively in SSPC. In the Notch-deficient mice, Ebf3 was downregulated, and it also showed abnormal upregulation in SSPC from middle-aged mice. Additional in vitro studies using wildtype SSPC showed that exposure to a Notch ligand increased Ebf3 expression, whereas a Notch inhibitor suppressed the Ebf3 increase, confirming that this molecule is downstream of Notch.

See Also "Vitamin D Pills Don’t Prevent Bone Fractures, Osteoporosis: Study"

“This opens up a whole new avenue to treat age related bone diseases,” said Leucht. “We have no drugs on the market that are affecting the stem and progenitor cell pool within the skeleton.” Translating these findings into therapeutics is an important goal for Leucht’s team moving forward. Chan believes that assessing if this pathway is also altered during human skeletal stem cell aging would be an important next step.

As a bone enthusiast, Leucht hopes that his study motivates others to study the skeletal tissue as well. “[From] all the tissues that are studied in basic science, bone is really getting so little attention, but it is such an amazing tissue,” he said. “It’s the most important tissue in our body. Without bones, we would be flat on the ground.”

  1. Remark LH, et al. Loss of Notch signaling in skeletal stem cells enhances bone formation with aging. Bone Res. 2023;11(1):50.
  2. Matsushita Y, et al. Skeletal stem cells for bone development and repair: Diversity matters. Curr Osteoporos Rep. 2020;18(3):189-198.
  3. Nishida S, et al. Number of osteoprogenitor cells in human bone marrow markedly decreases after skeletal maturation. J Bone Miner Metab. 1999;17(3):171-177.
  4. Josephson AM, et al. Age-related inflammation triggers skeletal stem/progenitor cell dysfunction. Proc Natl Acad Sci U S A. 2019;116(14):6995-7004.

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Meet the Author

  • Black and white portrait by Mariella Bodemeier Loayza Careaga, PhD

    Mariella Bodemeier Loayza Careaga, PhD

    Mariella is an assistant editor at The Scientist. She has a background in neuroscience, and her work has appeared in Drug Discovery News and Massive Science.
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