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糖皮质激素通过Hdac4/Foxc1轴调节Srsf1的表达，以诱导成骨细胞凋亡。

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

作者信息

Luo Hong, Wang Tao, Xie Zhihong, Li Fanchao, Yang Chengyou, Dong Wentao, Wu Jianhua, Wang Qiang, Xu Fengyang, Liu Jiong, Zhang Fei, Peng Wuxun

机构信息

Department of Orthopedics and Emergency, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.

Laboratory of Emergency Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.

出版信息

Commun Biol. 2025 Apr 4;8(1):566. doi: 10.1038/s42003-025-07989-x.

DOI:10.1038/s42003-025-07989-x
PMID:40186004
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11971326/
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.

摘要

进一步研究糖皮质激素（GC）诱导成骨细胞（OB）凋亡的机制对于预防和治疗GC诱导的骨质疏松症和骨坏死非常重要。在GC诱导的OB凋亡过程中，富含丝氨酸/精氨酸的剪接因子1（Srsf1）的表达呈剂量依赖性下调。敲低Srsf1显著促进GC诱导的OB凋亡，而Srsf1的过表达则显著抑制GC诱导的OB凋亡。机制上，GC诱导OB中组蛋白去乙酰化酶4（Hdac4）上调，并通过降低Foxc1启动子区域的组蛋白H3赖氨酸9乙酰化（H3K9ac）和H3K27ac水平来抑制转录激活因子叉头框C1（Foxc1）的表达，从而下调Srsf1。接下来，SRSF1通过调节Bcl-2修饰因子（Bmf）的可变剪接来调节GC诱导的OB凋亡。从可变剪接的角度来看，本研究表明Srsf1及其调控机制可能成为预防和治疗GC诱导的骨质疏松症和骨坏死的新靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2fb/11971326/ca9dd393edcb/42003_2025_7989_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2fb/11971326/4f56728bc60e/42003_2025_7989_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2fb/11971326/16efdaddb589/42003_2025_7989_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2fb/11971326/e5bbd13a5176/42003_2025_7989_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2fb/11971326/c7cfc26ecfc5/42003_2025_7989_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2fb/11971326/4d3ac5390dec/42003_2025_7989_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2fb/11971326/20930791bcb6/42003_2025_7989_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2fb/11971326/de5176b852f7/42003_2025_7989_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2fb/11971326/ca9dd393edcb/42003_2025_7989_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2fb/11971326/4f56728bc60e/42003_2025_7989_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2fb/11971326/16efdaddb589/42003_2025_7989_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2fb/11971326/e5bbd13a5176/42003_2025_7989_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2fb/11971326/c7cfc26ecfc5/42003_2025_7989_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2fb/11971326/4d3ac5390dec/42003_2025_7989_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2fb/11971326/20930791bcb6/42003_2025_7989_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2fb/11971326/de5176b852f7/42003_2025_7989_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2fb/11971326/ca9dd393edcb/42003_2025_7989_Fig8_HTML.jpg

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