title: miR-203 inhibits the traumatic heterotopic ossification by targeting Runx2.
abstract: Emerging evidence has indicated that dysregulated microRNAs (miRNAs) have an important role in bone formation. However, the pathophysiological role of miRNAs in traumatic heterotopic ossification (HO) remains to be elucidated. Using gene expression profile analyses and subsequent confirmation with real-time PCR assays, we identified the decreased expression of miRNA-203 (miR-203) and increased expression of Runx2 as responses to the development of traumatic HO. We found that miR-203 expression was markedly higher in primary and recurrent HO tissues than in normal bones. The upregulation of miR-203 significantly decreased the level of Runx2 expression, whereas miR-203 downregulation increased Runx2 expression. Mutation of the putative miR-203-binding sites in Runx2 mRNA abolished miR-203-mediated repression of Runx2 3'-untranslated region luciferase reporter activity, indicating that Runx2 is an important target of miR-203 in osteoblasts. We also found that miR-203 is negatively correlated with osteoblast differentiation. Furthermore, in vitro osteoblast activity and matrix mineralization were promoted by antagomir-203 and decreased by agomir-203. We showed that miR-203 suppresses osteoblast activity by inhibiting the β-catenin and extracellular signal-regulated kinase pathways. Moreover, using a tenotomy mouse HO model, we found an inhibitory role of miR-203 in regulating HO in vivo; pretreatment with antagomiR-203 increased the development of HO. These data suggest that miR-203 has a crucial role in suppressing HO by directly targeting Runx2 and that the therapeutic overexpression of miR-203 may be a potential strategy for treating traumatic HO.
authors: Department of Orthopaedic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China.
authors: Bing
authors: B
authors: Tu
authors: Department of Orthopaedic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China.
authors: Shen
authors: S
authors: Liu
authors: Department of Orthopaedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
authors: Bo
authors: B
authors: Yu
authors: Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors: Jing
authors: J
authors: Zhu
authors: Department of Orthopaedic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China.
authors: Hongjiang
authors: H
authors: Ruan
authors: Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Tingting
authors: T
authors: Tang
authors: Department of Orthopaedic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China.
authors: Cunyi
authors: C
authors: Fan
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009999:Ossification, Heterotopic / Q000150:complications / Q000235:genetics* / Q000473:pathology; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D014947:Wounds and Injuries / Q000150:complications*; D055815:Young Adult; D051176:beta Catenin / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D050659:Core Binding Factor Alpha 1 Subunit; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; D051176:beta Catenin; D048049:Extracellular Signal-Regulated MAP Kinases