SMAD4 transcriptionally activates GCN5 to inhibit apoptosis and promote osteogenic differentiation in dexamethasone-induced human bone marrow mesenchymal stem cells

被引:2
作者
Lu, Zhihua [1 ]
Han, Kuijing [2 ,3 ]
机构
[1] Yangzhou Polytech Coll, Med Sch, Yangzhou 225009, Jiangsu, Peoples R China
[2] Northern Jiangsu Peoples Hosp, Dept Orthoped, Yangzhou 225001, Jiangsu, Peoples R China
[3] Yangzhou Univ, Clin Med Coll, Yangzhou 225001, Jiangsu, Peoples R China
关键词
Steroid-induced osteonecrosis of the femoral; head; GCN5; SMAD4; Apoptosis; Osteogenic differentiation; STEROID-INDUCED OSTEONECROSIS; GROWTH-FACTOR-BETA; MORPHOGENETIC PROTEIN; FEMORAL-HEAD; EXPRESSION;
D O I
10.1016/j.steroids.2022.108969
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background: Steroid-induced osteonecrosis of the femoral head (SONFH) is a serious complication caused by long-term or excessive use of glucocorticoids (GCs). General control non-derepressible 5 (GCN5) has been reported to be lowly expressed in bone tissue. Therefore, this paper attempts to investigate the role of GCN5 in SONFH and identify the potential regulatory mechanism.Experimental design: Following human bone mesenchymal stem cells (hBMSCs) being stimulated with dexamethasone (Dex), GCN5 expression was detected using RT-qPCR and western blotting. Then, GCN5 was over expressed and cell viability was assessed by cell counting kit and lactate dehydrogenase kit. Cell apoptosis was determined with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and the expression of apoptosis-related proteins was evaluated using western blotting. Alkaline phosphatase (ALP) staining and alizarin red staining were adopted for the analysis of osteogenic differentiation. Additionally, the relationship between small mothers against decapentaplegic protein 4 (SMAD4) and GCN5 was predicted by hTFtarget website and verified by luciferase reporter-and chromatin immunoprecipitation (ChIP) assays. Subsequently, SMAD4 was silenced to determine cell viability, apoptosis and osteogenic differentiation in Dex-induced hBMSCs with GCN5 upregulation.Results: GCN5 expressed lower in hBMSCs exposed to Dex. GCN5 overexpression elevated cell viability, attenuated apoptosis and promoted osteogenic differentiation of hBMSCs. Additionally, SMAD4 transcriptionally activated GCN5 and upregulated GCN5 expression. While SMAD4 knockdown reversed the protective effects of GCN5 overexpression on Dex-induced cell viability loss, apoptosis increase and osteogenic differentiation inhibition in hBMSCs.Conclusions: SMAD4 transcriptionally activated GCN5 to inhibit apoptosis and promote osteogenic differentiation in Dex-induced hBMSCs.
引用
收藏
页数:9
相关论文
共 31 条
[1]   Reciprocal effect of microRNA-224 on osteogenesis and adipogenesis in steroid-induced osteonecrosis of the femoral head [J].
Cao, Yuanwu ;
Jiang, Chang ;
Wang, Xinyuan ;
Wang, Hao ;
Yan, Zuoqin ;
Yuan, Hengfeng .
BONE, 2021, 145
[2]  
Chan K L, 2012, Open Orthop J, V6, P449, DOI 10.2174/1874325001206010449
[3]   Dexamethasone induces osteoblast apoptosis through ROS-PI3K/AKT/ GSK3β signaling pathway [J].
Deng, Shuang ;
Dai, Guo ;
Chen, Sen ;
Nie, Zhigang ;
Zhou, Jianlin ;
Fang, Hongsong ;
Peng, Hao .
BIOMEDICINE & PHARMACOTHERAPY, 2019, 110 :602-608
[4]   Osteogenic Effect of tsRNA-10277-Loaded Exosome Derived from Bone Mesenchymal Stem Cells on Steroid-Induced Osteonecrosis of the Femoral Head [J].
Fang, Shanhong ;
He, Tianmin ;
Jiang, Jiarun ;
Li, Yongfeng ;
Chen, Peng .
DRUG DESIGN DEVELOPMENT AND THERAPY, 2020, 14 :4579-4591
[5]   Decreased Osteogenic Activity of Mesenchymal Stem Cells in Patients With Corticosteroid-Induced Osteonecrosis of the Femoral Head [J].
Houdek, Matthew T. ;
Wyles, Cody C. ;
Packard, Benjamin D. ;
Terzic, Andre ;
Behfar, Atta ;
Sierra, Rafael J. .
JOURNAL OF ARTHROPLASTY, 2016, 31 (04) :893-898
[6]  
Jiang TR, 2015, INT J CLIN EXP PATHO, V8, P2946
[7]   Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation [J].
Jin, Qihuang ;
Yu, Li-Rong ;
Wang, Lifeng ;
Zhang, Zhijing ;
Kasper, Lawryn H. ;
Lee, Ji-Eun ;
Wang, Chaochen ;
Brindle, Paul K. ;
Dent, Sharon Y. R. ;
Ge, Kai .
EMBO JOURNAL, 2011, 30 (02) :249-262
[8]   Epigenetic inhibition of Wnt pathway suppresses osteogenic differentiation of BMSCs during osteoporosis [J].
Jing, Huan ;
Su, Xiaoxia ;
Gao, Bo ;
Shuai, Yi ;
Chen, Ji ;
Deng, Zhihong ;
Liao, Li ;
Jin, Yan .
CELL DEATH & DISEASE, 2018, 9
[9]   Desferoxamine protects against glucocorticoid-induced osteonecrosis of the femoral head via activating HIF-1α expression [J].
Jing, Xingzhi ;
Du, Ting ;
Yang, Xiaoxia ;
Zhang, Weimin ;
Wang, Guodong ;
Liu, Xiaoyang ;
Li, Tao ;
Jiang, Zhensong .
JOURNAL OF CELLULAR PHYSIOLOGY, 2020, 235 (12) :9864-9875
[10]   TRANSFORMING GROWTH-FACTOR-BETA AND THE INITIATION OF CHONDROGENESIS AND OSTEOGENESIS IN THE RAT FEMUR [J].
JOYCE, ME ;
ROBERTS, AB ;
SPORN, MB ;
BOLANDER, ME .
JOURNAL OF CELL BIOLOGY, 1990, 110 (06) :2195-2207