Effects of miR-335-5p in modulating osteogenic differentiation by specifically downregulating Wnt antagonist DKK1
Reads0
Chats0
TLDR
In this paper, a series of studies including luciferase reporter assays, micro-RNA microarray, site-specific mutations, and gain-and loss-of-function analyses were performed to investigate the molecular mechanisms underlying the developmental stage-specific regulation of the DKK1 protein level.Abstract:
Dickkopf-related protein 1 (DKK1) is essential to maintain skeletal homeostasis as an inhibitor of Wnt signaling and osteogenic differentiation. The purpose of this study was to investigate the molecular mechanisms underlying the developmental stage-specific regulation of the DKK1 protein level. We performed a series of studies including luciferase reporter assays, micro-RNA microarray, site-specific mutations, and gain- and loss-of-function analyses. We found that the DKK1 protein level was regulated via DKK1 3' UTR by miRNA control, which was restricted to osteoblast-lineage cells. As a result of decreased DKK1 protein level by miR-335-5p, Wnt signaling was enhanced, as indicated by elevated GSK-3β phosphorylation and increased β-catenin transcriptional activity. The effects of miR-335-5p were reversed by anti-miR-335-5p treatment, which downregulated endogenous miR-335-5p. In vivo studies showed high expression levels of miR-335-5p in osteoblasts and hypertrophic chondrocytes of mouse embryos, indicating a pivotal role of miR-335-5p in regulating bone development. In conclusion, miR-335-5p activates Wnt signaling and promotes osteogenic differentiation by downregulating DKK1. This cell- and development-specific regulation is essential and mandatory for the initiation and progression of osteogenic differentiation. miR-335-5p proves to be a potential and useful targeting molecule for promoting bone formation and regeneration.read more
Citations
More filters
Journal ArticleDOI
MicroRNA control of bone formation and homeostasis
Jane B. Lian,Gary S. Stein,Andre J. van Wijnen,Janet L. Stein,Mohammad Q. Hassan,Tripti Gaur,Ying Zhang +6 more
TL;DR: Characterization of miRNAs that operate through tissue-specific transcription factors in osteoblast and osteoclast lineage cells, as well as intricate feedforward and reverse loops, has provided novel insights into the supervision of signaling pathways and regulatory networks controlling normal bone formation and turnover.
Journal ArticleDOI
miR-214 targets ATF4 to inhibit bone formation
Xiaogang Wang,Baosheng Guo,Baosheng Guo,Qi Li,Jiang Peng,Zhijun Yang,Aiyuan Wang,Dong Li,Zhibo Hou,Ke Lv,Guanghan Kan,Hongqing Cao,Heng Wu,Heng Wu,Jinping Song,Xiaohua Pan,Qiao Sun,Shukuan Ling,Yuheng Li,Mu Zhu,Pengfei Zhang,Songlin Peng,Xiaoqing Xie,Tao Tang,An Hong,Zhaoxiang Bian,Yanqiang Bai,Aiping Lu,Yinghui Li,Fuchu He,Ge Zhang,Ge Zhang,Yingxian Li +32 more
TL;DR: Elevated miR-214 levels correlated with a lower degree of bone formation in bone specimens from aged patients with fractures, and in vitro osteoblast activity and matrix mineralization were promoted by antagomir-214 and decreased by agomIR-214, and mi R-214 directly targeted ATF4 to inhibit osteoblasts activity.
Journal ArticleDOI
TGF-β/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation
TL;DR: Accumulating evidence indicates that Runx2 is the key integrator, whereas Hh is a possible modulator, miRNAs are regulators, and β-catenin is a mediator/regulator within the extensive intracellular network.
Journal ArticleDOI
Liposomes in tissue engineering and regenerative medicine
TL;DR: The potential role of liposomes as a platform for the sustained and local delivery of bioactive agents for tissue engineering and regenerative medicine approaches is highlighted.
Journal ArticleDOI
Wnt signaling in bone formation and its therapeutic potential for bone diseases
Jeong Hwan Kim,Xing Liu,Jinhua Wang,Xiang Chen,Hongyu Zhang,Stephanie H. Kim,Jing Cui,Ruidong Li,Wenwen Zhang,Yuhan Kong,Jiye Zhang,Wei Shui,Joseph D. Lamplot,Mary Rose Rogers,Chen Zhao,Ning Wang,Prashant Rajan,Justin Tomal,Joseph Statz,Ningning Wu,Hue H. Luu,Rex C. Haydon,Tong-Chuan He +22 more
TL;DR: The present review discusses the role of the Wnt signaling pathway in osteogenesis and examines its targeted therapeutic potential and indicates it requires cautious approach due to risks of tumorigenesis.
References
More filters
Journal ArticleDOI
MicroRNAs: Genomics, Biogenesis, Mechanism, and Function
TL;DR: Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.
Journal ArticleDOI
The functions of animal microRNAs
TL;DR: Evidence is mounting that animal miRNAs are more numerous, and their regulatory impact more pervasive, than was previously suspected.
Journal ArticleDOI
Prediction of Mammalian MicroRNA Targets
TL;DR: The predicted regulatory targets of mammalian miRNAs were enriched for genes involved in transcriptional regulation but also encompassed an unexpectedly broad range of other functions.
Journal ArticleDOI
Osf2/Cbfa1: A Transcriptional Activator of Osteoblast Differentiation
TL;DR: Cloned cDNA encoding Osf2/Cbfa1 is identified as an osteoblast-specific transcription factor and as a regulator of osteoblasts differentiation.
Journal ArticleDOI
Human MicroRNA Targets
Bino John,Anton J. Enright,Anton J. Enright,Alexei A. Aravin,Thomas Tuschl,Chris Sander,Debora S. Marks +6 more
TL;DR: This work has predicted target sites on the 3′ untranslated regions of human gene transcripts for all currently known 218 mammalian miRNAs to facilitate focused experiments and suggests that miRNA genes, which are about 1% of all human genes, regulate protein production for 10% or more of allhuman genes.