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

Abstract

Further study of the mechanism of glucocorticoid (GC)-induced osteoblast (OB) apoptosis is highly important for the prevention and treatment of GC-induced osteoporosis and osteonecrosis. Serine/arginine-rich splicing factor 1 (Srsf1) expression was downregulated in a dose-dependent manner during GC-induced OB apoptosis. Knockdown of Srsf1 significantly promotes GC-induced OB apoptosis, while overexpression of Srsf1 significantly inhibits GC-induced OB apoptosis. Mechanistically, GC induces the up-regulation of histone deacetylase 4 (Hdac4) in OB, and inhibits the expression of transcription activator forkhead box C1 (Foxc1) by reducing the levels of histone H3 lysine 9 acetylation (H3K9ac) and H3K27ac in the promoter region of Foxc1, thereby down-regulating Srsf1. Next, SRSF1 regulates GC-induced OB apoptosis by regulating Bcl-2 modifying factor (Bmf) alternative splicing. From the perspective of alternative splicing, this study demonstrates that Srsf1 and its regulatory mechanism may serve as a new target for the prevention and treatment of GC-induced osteoporosis and osteonecrosis.