Splicing factor YBX1 regulates bone marrow stromal cell fate during aging

Area of Science:

• Biochemistry
• Cell Biology
• Gerontology

Background:

• Cellular senescence and altered differentiation of bone marrow stromal cells (BMSCs) contribute to age-related bone loss.
• Alternative splicing (AS) is a key posttranscriptional regulatory pathway influencing gene expression and cellular senescence.

Purpose of the Study:

• To investigate the role of splicing factors, specifically Y-box binding protein 1 (YBX1), in BMSCs during aging.
• To explore the therapeutic potential of targeting YBX1 for age-related bone loss.

Main Methods:

• Examined YBX1 expression in aging BMSCs from mice and humans.
• Assessed the impact of YBX1 deficiency and overexpression on BMSC senescence and osteogenic differentiation.
• Investigated the effect of sciadopitysin on YBX1 levels and bone loss in aged mice.

Main Results:

• YBX1 expression decreased with age in BMSCs.
• YBX1 deficiency led to mis-splicing of key genes, promoting BMSC senescence and impairing differentiation.
• Ybx1 deletion accelerated bone loss, while overexpression enhanced bone formation.
• The compound sciadopitysin protected YBX1 from degradation and reduced bone loss in aged mice.

Conclusions:

• YBX1 is crucial for maintaining BMSC function and fate through precise RNA splicing control.
• YBX1 deficiency contributes significantly to age-related osteoporosis.
• Targeting YBX1 degradation presents a promising therapeutic strategy for osteoporosis.