title: MicroRNA-1 regulates chondrocyte phenotype by repressing histone deacetylase 4 during growth plate development.
abstract: MicroRNAs (miRs) are noncoding RNAs (17-25 nt) that control translation and/or mRNA degradation. Using Northern blot analysis, we identified that miR-1 is specifically expressed in growth plate cartilage in addition to muscle tissue, but not in brain, intestine, liver, or lung. We obtained the first evidence that miR-1 is highly expressed in the hypertrophic zone of the growth plate, with an 8-fold increase compared with the proliferation zone; this location coincides with the Ihh and Col X expression regions in vivo. MiR-1 significantly induces chondrocyte proliferation and differentiation. We further identified histone deacetylase 4 (HDAC4) as a target of miR-1. HDAC4 negatively regulates chondrocyte hypertrophy by inhibiting Runx2, a critical transcription factor for chondrocyte hypertrophy. MiR-1 inhibits both endogenous HDAC4 protein by 2.2-fold and the activity of a reporter gene bearing the 3'-untranslated region (UTR) of HDAC4 by 3.3-fold. Conversely, knockdown of endogenous miR-1 relieves the repression of HDAC4. Deletion of the miR-1 binding site in HDAC4 3'-UTR or mutated miR-1 abolishes miR-1-mediated inhibition of the reporter gene activity. Overexpression of HDAC4 reverses miR-1 induction of chondrocyte differentiation markers Col X and Ihh. HDAC4 inhibits Runx2 promoter activity in a dosage-dependent manner. Thus, miR-1 plays an important role in the regulation of the chondrocyte phenotype during the growth plate development via direct targeting of HDAC4.
authors.affiliation: Department of Orthopaedics, Second Hospital of Shanxi Medical University, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Taiyuan, China; and.
authors.forename: Pengcui
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Orthopaedics, Second Hospital of Shanxi Medical University, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Taiyuan, China; and.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Orthopaedics and.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Department of Orthopaedics and.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Surgery, Warren Alpert Medical School of Brown University/Rhode Island Hospital (RIH), Providence, Rhode Island, USA.
authors.forename: Tingcun
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Orthopaedics and.
authors.forename: Changqi
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Orthopaedics, Second Hospital of Shanxi Medical University, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Taiyuan, China; and Department of Orthopaedics and lei_wei@brown.edu.
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D002642:Chick Embryo; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism; D020219:Chondrogenesis / Q000502:physiology*; D024121:Collagen Type X / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006132:Growth Plate / Q000166:cytology* / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D024121:Collagen Type X; D050659:Core Binding Factor Alpha 1 Subunit; D053823:Hedgehog Proteins; C509246:IHH protein, human; C544547:MIRN1 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C493709:RUNX2 protein, human; D012097:Repressor Proteins; D008156:Luciferases; C400300:HDAC4 protein, human; D006655:Histone Deacetylases
keywords: HDAC4; Runx2; collagen X; differentiation