FKBP5 promotes osteogenic differentiation of mesenchymal stem cells through type-I interferon pathway Inhibition

Area of Science:

• Stem cell biology
• Molecular mechanisms of bone formation
• Bioinformatics and genomics

Background:

• Decreased osteogenesis in bone marrow mesenchymal stem cells (BMSCs) contributes to bone loss.
• The precise molecular mechanisms regulating BMSC osteogenesis remain incompletely understood.

Purpose of the Study:

• To identify key genes involved in BMSC osteogenic differentiation.
• To elucidate the molecular pathways regulating BMSC osteogenesis.

Main Methods:

• Bioinformatic analysis of public Gene Expression Omnibus (GEO) datasets.
• RNA sequencing (RNA-seq) for gene expression profiling.
• In vitro experiments involving gene knockdown and overexpression in BMSCs.
• In vivo studies using mouse models (hydroxyapatite scaffold and drilled tibiae).

Main Results:

• FK506 Binding Protein 5 (FKBP5) expression is significantly upregulated during BMSC osteogenic differentiation.
• FKBP5 positively regulates osteogenesis, as evidenced by increased osteogenic markers and Alizarin Red S staining upon overexpression and decreased markers upon knockdown.
• Downregulation of FKBP5 activates the IFNα/β signaling pathway, and FKBP5 overexpression mitigates the inhibitory effects of IFNβ.
• Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2), an interferon-stimulated gene, negatively regulates BMSC osteogenesis.
• IFIT2 knockdown rescued the impaired osteogenesis caused by FKBP5 downregulation.
• In vivo studies confirmed the positive role of FKBP5 in osteogenesis.

Conclusions:

• FKBP5 plays a beneficial role in the osteogenesis of BMSCs.
• The FKBP5/IFIT2 axis is a critical regulator of BMSC osteogenesis.
• These findings offer potential therapeutic targets for bone diseases such as osteoporosis and fractures.