In a recent study conducted on mice by researchers from NYU Grossman School of Medicine, it was discovered that as aging progresses, a critical cellular signal necessary for skeletal development increases, leading to weakened bones; however, blocking this signaling pathway, known as Notch, in aging skeletal stem cells resulted in a substantial boost in bone mass and the restoration of lost bone-healing capabilities associated with aging.
The study focuses on immature stem cells, which can develop into multiple cell types. Tissues like bone maintain pools of these stem cells throughout adulthood to replace damaged cells and aid in healing. Skeletal stem and progenitor cells (SSCPs) in the bone marrow can become either bone-forming cells (osteoblasts) or fat-forming cells (adipocytes). As tissues age, these cells tend to become fat cells more than bone cells, increasing the risk of bone fractures. The study aims to clarify the cellular signals involved in this process, with implications for understanding and potentially addressing age-related bone weakening.
During the study, published in Bone Research on September 27, NYU Langone researchers investigated the aging process in mice and discovered that the Notch pathway becomes excessively active in SSCPs, pushing them toward a fate that promotes fat accumulation in the bone marrow. However, when the scientists engineered mice to lack Nicastrin, a key component of the Notch signaling pathway, the SSCP cells reverted to the bone-forming pathway, resulting in increased bone formation, surpassing even the levels seen in young mice. While the complex Notch signaling is not an ideal target for drug therapy, the study identified a protein called Ebf3 as a potential drug target to modulate the Notch signal and influence bone health.
According to study authors, aging is often associated with a decline in the ability of stem cells to transform into bone-forming cells, contributing to skeletal problems commonly seen in older individuals. Unfortunately, there are currently no treatments available to restore or maintain the bone-building capacity in aging SSCPs. Therefore it's crucial to understand the mechanisms behind the transition from bone to fat accumulation in the skeleton to support healthier aging. To investigate this, the research team employed a technique called single-cell RNA sequencing, which involves analyzing the genetic information within individual cells. By examining RNA profiles in single cells from both young and aged mouse bones, they uncovered that Notch signaling becomes more active in SSPCs as they age, shedding light on the underlying changes that affect bone health during aging.
Notch signaling plays a crucial role in the development of various tissues during fetal development, but it is usually suppressed in adulthood to maintain healthy tissue function. Abnormal reactivation of developmental processes, often associated with diseases like cancer and the aging process, can occur when genetic systems (specifically, heterochromatin) that normally block access to certain genes become compromised. Therefore, the study's discovery that genes related to Notch signaling were excessively activated could potentially unveil the mechanisms behind the deterioration observed in other tissues and organs, shedding light on disease processes related to these abnormalities.
The findings of this study offer potential insights into age-related skeletal degeneration and provide a promising avenue for future research and the development of therapeutic interventions to prevent osteoporosis and other bone-related disorders. Dr. Philipp Leucht, one of the researchers involved in the study, stated, "Our findings reveal that Notch in skeletal stem cells becomes abnormal with age, and that blocking it prevents age-related skeletal degeneration." He also noted the therapeutic potential of reprogramming adult stem cells as a source of bone-making cells in healing-compromised individuals and expressed hope to confirm the value of Ebf3 as a drug target in preventing osteoporosis in future studies.
