Biological functions of miR-29b contribute to positive regulation of osteoblast differentiation
Department of Cell Biology
Medical Subject Headings
3' Untranslated Regions; 3T3 Cells; Animals; Blotting, Western; Cell Differentiation; DNA Primers; Gene Expression Profiling; Mice; MicroRNAs; Osteoblasts; Plasmids; RNA, Messenger; Rats; Reverse Transcriptase Polymerase Chain Reaction; Transfection
Bone tissue arises from mesenchymal cells induced into the osteoblast lineage by essential transcription factors and signaling cascades. MicroRNAs regulate biological processes by binding to mRNA 3'-untranslated region (UTR) sequences to attenuate protein synthesis. Here we performed microRNA profiling and identified miRs that are up-regulated through stages of osteoblast differentiation. Among these are the miR-29, miR-let-7, and miR-26 families that target many collagens and extracellular matrix proteins. We find that miR-29b supports osteoblast differentiation through several mechanisms. miR-29b decreased and anti-miR-29b increased activity of COL1A1, COL5A3, and COL4A2 3'-UTR sequences in reporter assays, as well as endogenous gene expression. These results support a mechanism for regulating collagen protein accumulation during the mineralization stage when miR-29b reaches peak levels. We propose that this mechanism prevents fibrosis and facilitates mineral deposition. Our studies further demonstrate that miR-29b promotes osteogenesis by directly down-regulating known inhibitors of osteoblast differentiation, HDAC4, TGFbeta3, ACVR2A, CTNNBIP1, and DUSP2 proteins through binding to target 3'-UTR sequences in their mRNAs. Thus, miR-29b is a key regulator of development of the osteoblast phenotype by targeting anti-osteogenic factors and modulating bone extracellular matrix proteins.
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Citation: J Biol Chem. 2009 Jun 5;284(23):15676-84. Epub 2009 Apr 2. Link to article on publisher's site