title: A program of microRNAs controls osteogenic lineage progression by targeting transcription factor Runx2.
abstract: Lineage progression in osteoblasts and chondrocytes is stringently controlled by the cell-fate-determining transcription factor Runx2. In this study, we directly addressed whether microRNAs (miRNAs) can control the osteogenic activity of Runx2 and affect osteoblast maturation. A panel of 11 Runx2-targeting miRNAs (miR-23a, miR-30c, miR-34c, miR-133a, miR-135a, miR-137, miR-204, miR-205, miR-217, miR-218, and miR-338) is expressed in a lineage-related pattern in mesenchymal cell types. During both osteogenic and chondrogenic differentiation, these miRNAs, in general, are inversely expressed relative to Runx2. Based on 3'UTR luciferase reporter, immunoblot, and mRNA stability assays, each miRNA directly attenuates Runx2 protein accumulation. Runx2-targeting miRNAs differentially inhibit Runx2 protein expression in osteoblasts and chondrocytes and display different efficacies. Thus, cellular context contributes to miRNA-mediated regulation of Runx2. All Runx2-targeting miRNAs (except miR-218) significantly impede osteoblast differentiation, and their effects can be reversed by the corresponding anti-miRNAs. These findings demonstrate that osteoblastogenesis is limited by an elaborate network of functionally tested miRNAs that directly target the osteogenic master regulator Runx2.
authors.affiliation: Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Rong-Lin
authors.initials: RL
authors.lastname: Xie
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stein
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D041681:NIH 3T3 Cells; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D050659:Core Binding Factor Alpha 1 Subunit; C551799:MIRN137 microRNA, mouse; D035683:MicroRNAs; D012333:RNA, Messenger; D008156:Luciferases