Argonaute (AGO) proteins play an essential role in mediating BMP9-induced osteogenic signaling in mesenchymal stem cells (MSCs)

Genes and Diseases

Sherwin H. Ho¹  Russell R. Reid²  Fang He³  Andrew Blake Tucker⁴  Jiaming Fan⁴  Deyao Shi⁴  Mikhail Pakvasa⁴  Na Ni⁵  Tong-Chuan He⁵  Le Shen⁶  Michael J. Lee⁷  Yukun Mao⁷  Connie Chen⁸  Hao Wang⁸  Linjuan Huang⁸  William Wagstaff⁸  Qing Liu⁸  Jian Yang⁸  Hue H. Luu⁸  Kai Fu⁸  Rex C. Haydon⁸  Lin Cai⁸ 

[1] Department of Orthopaedic Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430022, PR China;Department of Spine Surgery, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, 410011, PR China;Departments of Nephrology, and Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China;Ministry of Education Key Laboratory of Diagnostic Medicine, and the School of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, PR China;Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA;Section of Plastic Surgery and Laboratory of Craniofacial Biology and Development, and Section of Surgical Research, Department of Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA;Departments of Spine Surgery and Musculoskeletal Tumor, and Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, 430072, PR China;Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA;

关键词: Argonaute (AGO) proteins;    BMP9;    Bone formation;    Lineage-specific differentiation;    Mesenchymal stem cells;    miRNA biogenesis;   

DOI  :  

来源: DOAJ

【 摘 要 】

As multipotent progenitor cells, mesenchymal stem cells (MSCs) can renew themselves and give rise to multiple lineages including osteoblastic, chondrogenic and adipogenic lineages. It's previously shown that BMP9 is the most potent BMP and induces osteogenic and adipogenic differentiation of MSCs. However, the molecular mechanism through which BMP9 regulates MSC differentiation remains poorly understood. Emerging evidence indicates that noncoding RNAs, especially microRNAs, may play important roles in regulating MSC differentiation and bone formation. As highly conserved RNA binding proteins, Argonaute (AGO) proteins are essential components of the multi-protein RNA-induced silencing complexes (RISCs), which are critical for small RNA biogenesis. Here, we investigate possible roles of AGO proteins in BMP9-induced lineage-specific differentiation of MSCs. We first found that BMP9 up-regulated the expression of Ago1, Ago2 and Ago3 in MSCs. By engineering multiplex siRNA vectors that express multiple siRNAs targeting individual Ago genes or all four Ago genes, we found that silencing individual Ago expression led to a decrease in BMP9-induced early osteogenic marker alkaline phosphatase (ALP) activity in MSCs. Furthermore, we demonstrated that simultaneously silencing all four Ago genes significantly diminished BMP9-induced osteogenic and adipogenic differentiation of MSCs and matrix mineralization, and ectopic bone formation. Collectively, our findings strongly indicate that AGO proteins and associated small RNA biogenesis pathway play an essential role in mediating BMP9-induced osteogenic differentiation of MSCs.

【 授权许可】

Unknown