title: ACVR1, a therapeutic target of fibrodysplasia ossificans progressiva, is negatively regulated by miR-148a.
abstract: Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder of skeletal malformations and progressive extraskeletal ossification. There is still no effective treatment for FOP. All FOP individuals harbor conserved point mutations in ACVR1 gene that are thought to cause ACVR1 constitutive activation and activate BMP signal pathway. The constitutively active ACVR1 is also found to be able to cause endothelial-to-mesenchymal transition (EndMT) in endothelial cells, which may cause the formation of FOP lesions. MicroRNAs (miRNAs) play an essential role in regulating cell differentiation. Here, we verified that miR-148a directly targeted the 3' UTR of ACVR1 mRNA by reporter gene assays and mutational analysis at the miRNA binding sites, and inhibited ACVR1 both at the protein level and mRNA level. Further, we verified that miR-148a could inhibit the mRNA expression of the Inhibitor of DNA binding (Id) gene family thereby suppressing the BMP signaling pathway. This study suggests miR-148a is an important mediator of ACVR1, thus offering a new potential target for the development of therapeutic agents against FOP.
authors.affiliation: Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.|Research Laboratory of Virology, Immunology & Bioinformatics, Northwest A & F University, Xianyang 712100, Shaanxi, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Song
authors.affiliation: Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Research Laboratory of Virology, Immunology & Bioinformatics, Northwest A & F University, Xianyang 712100, Shaanxi, China.
authors.forename: Junge
authors.initials: J
authors.lastname: Wen
authors.affiliation: Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.
authors.forename: Shunai
authors.initials: S
authors.lastname: Liu
authors.affiliation: Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Gao
authors.affiliation: Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Research Laboratory of Virology, Immunology & Bioinformatics, Northwest A & F University, Xianyang 712100, Shaanxi, China.
authors.forename: Deli
authors.initials: D
authors.lastname: Zhang
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D009221:Myositis Ossificans / Q000235:genetics* / Q000628:therapy; D012689:Sequence Homology, Nucleic Acid; D014407:Tumor Cells, Cultured
chemical_list: C550570:MIRN148 microRNA, human; D035683:MicroRNAs; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I