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

The decreased osteogenesis of bone marrow mesenchymal stem cells (BMSCs) is an important factor causing bone loss. Nevertheless, its deep molecular mechanism has still not been fully clarified. To elucidate the regulatory mechanisms underlying BMSC osteogenesis, we conducted a bioinformatics screen using public datasets from the Gene Expression Omnibus (GEO) database to identify genes displaying significant expression dynamics during the osteogenic differentiation of BMSCs. We observed a significant upregulation of FK506 Binding Protein 5 (FKBP5) expression during the osteogenic differentiation of BMSCs. Besides, knockdown and overexpression of FKBP5 could reduce and increase osteogenic markers and Alizarin Red S (ARS) staining, respectively. Enrichment analysis of RNA sequencing (RNA-seq) demonstrated that downregulation of FKBP5 activated IFNα/β signaling pathway. FKBP5 overexpression relieved the inhibitory effect of IFNβ on osteogenesis. In addition, one of the upregulated interferon-stimulated genes (ISG), interferon-induced protein with tetratricopeptide repeats 2 (IFIT2), negatively regulated osteogenesis of BMSCs. IFIT2 knockdown rescued negative effect on osteogenesis caused by downregulation of FKBP5. Hydroxyapatite scaffold implanted in nude mice and drilled tibiae model in C57BL/6 mice confirmed positive role of FKBP5 in osteogenesis in vivo. Therefore, we determined the beneficial effect of FKBP5 on osteogenesis of BMSCs and validated the critical role of FKBP5/IFIT2 axis in this process. These findings might contribute to comprehension and treatment of bone diseases, like osteoporosis and bone fracture.