A CREB1-miR-181a-5p loop regulates the pathophysiologic features of bone marrow stromal cells in fibrous dysplasia of bone

Molecular Medicine

Jialin Lin¹  Ling Xu¹  Hongbing Jiang²  Yu Fu²  Zhili Xin³  Xin Shen³  Ziji Ling³  Hanyu Xie³  Tao Xiao⁴ 

[1] Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, No.136, Hanzhong Road, 210029, Nanjing, Jiangsu Province, China;Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, No.136, Hanzhong Road, 210029, Nanjing, Jiangsu Province, China;Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, 210029, Nanjing, China;Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, 210029, Nanjing, China;Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, No.136, Hanzhong Road, 210029, Nanjing, Jiangsu Province, China;Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, 210029, Nanjing, China;Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, No.136, Hanzhong Road, 210029, Nanjing, Jiangsu Province, China;Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, 210029, Nanjing, China;Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, 210008, Nanjing, China;

关键词: CREB;    miR-181a-5p;    Bone marrow stromal cells;    Fibrous dysplasia;    Proliferation;    Apoptosis;   

DOI  :  10.1186/s10020-021-00341-z

来源: Springer

【 摘 要 】

BackgroundFibrous dysplasia (FD) is a bone marrow stromal cell (BMSC) disease caused by activating mutations of guanine nucleotide-binding protein alpha-stimulating activity polypeptide (GNAS) and is characterized by increased proliferative activity and disrupted osteogenesis of BMSCs. However, the molecular mechanisms regulating the pathophysiologic features of BMSCs in FD remain unknown. This study aimed to identify and verify the roles of the CREB1-miR-181a-5p regulatory loop in FD pathophysiology.MethodsMicroRNA (miRNA) sequencing analysis was used to identify the possible miRNAs implicated in FD. The proliferation, apoptosis, and osteogenic differentiation of BMSCs, as well as the osteoclast-induced phenotype, were measured and compared after exogenous miR-181a-5p transfection into FD BMSCs or miR-181a-5p inhibitor transfection into normal BMSCs. Chromatin immunoprecipitation and luciferase reporter assays were performed to verify the interactions between CREB1 and miR-181a-5p and their effects on the FD pathological phenotype.ResultsCompared to normal BMSCs, FD BMSCs showed decreased miR-181a-5p levels and exhibited increased proliferative activity, decreased apoptotic capacity, and impaired osteogenesis. FD BMSCs also showed a stronger osteoclast activation effect. miR-181a-5p overexpression reversed the pathophysiologic features of FD BMSCs, whereas miR-181a-5p suppression induced an FD-like phenotype in normal BMSCs. Mechanistically, miR-181a-5p was the downstream target of CREB1, and CREB1 was posttranscriptionally regulated by miR-181a-5p.ConclusionsOur study identifies that the interaction loop between CREB1 and miR-181a-5p plays a crucial role in regulating the pathophysiologic features of FD BMSCs. MiR-181a-5p may be a potential therapeutic target for the treatment of FD.

【 授权许可】

CC BY