Document Detail

Vitamin D activation of functionally distinct regulatory miRNAs in primary human osteoblasts.
MedLine Citation:
PMID:  23362149     Owner:  NLM     Status:  MEDLINE    
When bound to the vitamin D receptor (VDR), the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is a potent regulator of osteoblast transcription. Less clear is the impact of 1,25D on posttranscriptional events in osteoblasts, such as the generation and action of microRNAs (miRNAs). Microarray analysis using replicate (n = 3) primary cultures of human osteoblasts (HOBs) identified human miRNAs that were differentially regulated by >1.5-fold following treatment with 1,25D (10 nM, 6 hours), which included miRNAs 637 and 1228. Quantitative reverse transcription PCR analyses showed that the host gene for miR-1228, low-density lipoprotein receptor-related protein 1 (LRP1), was coinduced with miR-1228 in a dose-dependent fashion following treatment with 1,25D (0.1-10 nM, 6 hours). By contrast, the endogenous host gene for miR-637, death-associated protein kinase 3 (DAPK3), was transcriptionally repressed by following treatment with 1,25D. Analysis of two potential targets for miR-637 and miR-1228 in HOB, type IV collagen (COL4A1) and bone morphogenic protein 2 kinase (BMP2K), respectively, showed that 1,25D-mediates suppression of these targets via distinct mechanisms. In the case of miR-637, suppression of COL4A1 appears to occur via decreased levels of COL4A1 mRNA. By contrast, suppression of BMP2K by miR-1228 appears to occur by inhibition of protein translation. In mature HOBs, small interfering RNA (siRNA) inactivation of miR-1228 alone was sufficient to abrogate 1,25D-mediated downregulation of BMP2K protein expression. This was associated with suppression of prodifferentiation responses to 1,25D in HOB, as represented by parallel decrease in osteocalcin and alkaline phosphatase expression. These data show for the first time that the effects of 1,25D on human bone cells are not restricted to classical VDR-mediated transcriptional responses but also involve miRNA-directed posttranscriptional mechanisms.
Thomas S Lisse; Rene F Chun; Sandra Rieger; John S Adams; Martin Hewison
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research     Volume:  28     ISSN:  1523-4681     ISO Abbreviation:  J. Bone Miner. Res.     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-05-22     Completed Date:  2013-12-09     Revised Date:  2014-06-03    
Medline Journal Info:
Nlm Unique ID:  8610640     Medline TA:  J Bone Miner Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1478-88     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 American Society for Bone and Mineral Research.
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MeSH Terms
Alkaline Phosphatase / biosynthesis,  genetics
Bone Density Conservation Agents / pharmacology*
Calcitriol / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Collagen Type IV / biosynthesis,  genetics
Death-Associated Protein Kinases / biosynthesis,  genetics
Dose-Response Relationship, Drug
Gene Expression Regulation / drug effects*,  physiology
Low Density Lipoprotein Receptor-Related Protein-1 / biosynthesis,  genetics
MicroRNAs / biosynthesis*,  genetics
Osteoblasts / cytology,  metabolism*
Osteocalcin / biosynthesis,  genetics
Protein Biosynthesis / drug effects,  physiology
RNA, Messenger / biosynthesis,  genetics
Time Factors
Transcription, Genetic / drug effects,  physiology
Grant Support
Reg. No./Substance:
0/Bone Density Conservation Agents; 0/COL4A1 protein, human; 0/Collagen Type IV; 0/LRP1 protein, human; 0/Low Density Lipoprotein Receptor-Related Protein-1; 0/MIRN1228 microRNA, human; 0/MIRN637 microRNA, human; 0/MicroRNAs; 0/RNA, Messenger; 104982-03-8/Osteocalcin; EC protein, human; EC Protein Kinases; EC Phosphatase; FXC9231JVH/Calcitriol

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