Turning back the hands of time on skeletal deterioration
The recent identification of signaling pathways that determine bone stem cell fate could lead to new therapeutic targets to reverse age-linked skeletal impairment.
A recent study led by researchers from NYU Grossman School of Medicine (NY, USA) identified age-related changes in cell signaling pathways that are associated with a change in the proportions of different cell types that reduce skeletal integrity. They then pinpointed promising therapeutic targets, using information derived from the preclinical investigations, that could lay the groundwork for drugs that lessen age-associated bone degradation, such as in conditions like osteoporosis.
Some tissues retain multipotent stem cells capable of forming specific cells relevant to that tissue type, which replace damaged or dysfunctional cells to maintain healthy tissue. One of these is bone tissue, which possesses skeletal stem and progenitor cells (SSCPs). These cells are located in the bone marrow and differentiate into both osteoblasts (bone-forming cells) and adipocytes (fat-forming cells).
As the body progressively ages, normal cellular processes begin to unravel. This is also the case in bone tissue, where the balance of SSPC differentiation into osteoblasts and adipocytes becomes skewed towards the latter, making bone weaker and more vulnerable to fracture.
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The research team wanted to identify the cellular signals that cause this age-dependent shift. An improved understanding of this mechanism could uncover novel therapeutic targets for age-associated tissue deterioration, which is especially important given that no drugs rescue or maintain the bone-making function in aging SSPCs.
The researchers first employed single-cell RNA sequencing to delineate differences in RNA transcripts between hindlimb bone cells of young and middle-aged mice. This revealed age-related upregulation of genes that are involved in the Notch signaling pathway.
Next, the team looked at the in vivo effect of disrupting Notch on SSPCs, which they did with conditional knockout mice that had Ncstn disrupted, the corresponding protein Nicastrin is an essential component of the signaling process. This resulted in increased SSPC differentiation into osteoblasts relative to adipocytes and enhanced bone regeneration in middle-aged mice.
Given that Notch is intertwined in many cellular pathways other than SSPC differentiation, it is not considered to be a good therapeutic target. However, the team identified a transcription factor, Ebf3, as a downstream target of Notch, which has a relatively restricted expression pattern and therefore makes it a potential target to combat age-related skeletal degeneration.
“Our findings reveal that Notch in skeletal stem cells becomes abnormal with age and that blocking it prevents age-related skeletal degeneration,” says corresponding author Philipp Leucht, the Raj-Sobti-Menon Associate Professor in the Department of Orthopedic Surgery and Cell Biology at NYU Langone Health (NY, USA), “The reprogramming of adult stem cells as a source of bone-making cells in healing-compromised people has profound therapeutic potential and we hope to confirm the value in future studies of Ebf3 as a drug target in preventing osteoporosis.”