Blocking Notch Signaling Pathway Prevents Age-Related Skeletal Degeneration

Researchers at NYU Grossman School of Medicine have discovered that the Notch signaling pathway plays a crucial role in age-related bone weakening in mice. This pathway, essential for skeletal stem cell development, becomes abnormally active with aging, increasing fat accumulation in bone marrow and weakening bones. The team’s findings were published in Bone Research earlier this week.

Skeletal stem and progenitor cells (SSCPs) in the bone marrow can differentiate into bone-making cells (osteoblasts) or fat-making cells (adipocytes). As tissues age, SSCP differentiation is skewed toward adipocytes, rendering bones more vulnerable to fractures.

By genetically engineering mice to lack Nicastrin, a core component of the Notch signaling pathway, the researchers reversed this process, encouraging bone formation even beyond what was observed in young mice.

While Notch signaling itself isn't a suitable target for drug therapy due to its involvement in multiple cellular pathways, the study identified a protein called Ebf3 as a potential drug target. Ebf3 carries the Notch signal forward and could be targeted by drugs to prevent age-related skeletal degeneration.

The loss of stem cell ability to become bone-making cells is a common factor in age-related skeletal deterioration, with no current therapeutics to counter it. Understanding the mechanisms behind bone-to-fat shifts in aging bones is crucial for prolonging healthy lifespans.

To address this challenge, the researchers used single-cell RNA sequencing to study young and aged mouse bones. This revealed that Notch signaling becomes elevated in SSCP cells during aging.

Notch signaling is critical for tissue development in embryos but is suppressed in adulthood for healthy tissue function. Abnormal reactivation of developmental processes, like Notch signaling, is linked to diseases and aging-related deterioration in various tissues and organs.