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Vitamin D activation of functionally distinct regulatory miRNAs in primary human osteoblasts.
MedLine Citation:
PMID:  23362149     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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 post-transcriptional events in osteoblasts, such as the generation and action of microRNAs (miRNAs). Microarray analysis using replicate (n = 3) primary cultures of human osteoblasts (HOB) identified human miRNAs that were differentially regulated by > 1.5-fold following treatment with 1,25D (10nM, 6 hrs), which included miRNAs 637 and 1228. RT-PCR analyses showed that the host gene for miR-1228, low density lipoprotein receptor-related protein 1 (LRP1), was co-induced with miR-1228 in a dose-dependent fashion following treatment with 1,25D (0.1 - 10nM, 6hrs). 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, siRNA inactivation of miR-1228 alone was sufficient to abrogate 1,25D-mediated down regulation of BMP2K protein expression. This was associated with suppression of pro-differentiation 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 post-transcriptional mechanisms. © 2013 American Society for Bone and Mineral Research.
Authors:
Thomas S Lisse; Rene F Chun; Sandra Rieger; John S Adams; Martin Hewison
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-29
Journal Detail:
Title:  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research     Volume:  -     ISSN:  1523-4681     ISO Abbreviation:  J. Bone Miner. Res.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-30     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8610640     Medline TA:  J Bone Miner Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2013 American Society for Bone and Mineral Research.
Affiliation:
Orthopaedic Hospital Research Center, University of California Los Angeles, Los Angeles, CA 90095, USA.
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