Glucocorticoids regulate the expression of Srsf1 through Hdac4/Foxc1 axis to induce apoptosis of osteoblasts

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Glucocorticoid (GC)-induced osteoporosis and osteonecrosis are significant clinical concerns.
• Understanding the mechanisms of GC-induced osteoblast (OB) apoptosis is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the role of Serine/arginine-rich splicing factor 1 (Srsf1) in GC-induced OB apoptosis.
• To elucidate the molecular mechanism by which GC affects Srsf1 expression and OB apoptosis.

Main Methods:

• Dose-dependent analysis of Srsf1 expression during GC treatment.
• Manipulation of Srsf1 levels (knockdown and overexpression) in OBs.
• Investigation of histone modifications (H3K9ac, H3K27ac) and gene expression (Hdac4, Foxc1).
• Analysis of Bcl-2 modifying factor (Bmf) alternative splicing.

Main Results:

• Srsf1 expression decreased in a dose-dependent manner with GC-induced OB apoptosis.
• Srsf1 knockdown exacerbated GC-induced OB apoptosis, while Srsf1 overexpression inhibited it.
• GC upregulated Hdac4 and reduced Foxc1 expression by decreasing histone acetylation at the Foxc1 promoter, leading to Srsf1 downregulation.
• SRSF1 regulates GC-induced OB apoptosis through Bmf alternative splicing.

Conclusions:

• Srsf1 plays a critical role in regulating GC-induced OB apoptosis.
• The mechanism involves GC-induced changes in Hdac4, Foxc1, and histone acetylation, impacting Srsf1 levels.
• Srsf1 and its regulatory pathway represent a potential therapeutic target for GC-induced bone pathologies.