title: MicroRNA-152 modulates the canonical Wnt pathway activation by targeting DNA methyltransferase 1 in arthritic rat model.
abstract: Rheumatoid arthritis (RA) is an autoimmune and progressive systemic disease of unknown etiology. Research shows that fibroblast-like synoviocytes (FLS) participate in the cartilage erosion, synovial hyperplasia, inflammatory cytokine secretion and suggests that fibroblast-like synoviocytes (FLS) display a crucial role in RA pathogenesis. Recent studies have suggested the role of the Wnt signaling pathway in the pathogenesis of RA. In previous study, we identified that increased methyl-CpG-binding protein 2 (MeCP2) reduced the secreted frizzled-related protein 4 (SFRP4) expression in FLS in Arthritic rat model and the DNA methyltransferase (DNMT) inhibitor 5-Aza-2'-deoxycytidine (5-azadC) could induce the SFRP4 expression, indicating that DNMT has a key role in the differential expression of SFRP4. MicroRNAs (MiRNAs), which are small non-coding RNAs, are involved in diverse biological functions, regulation of gene expression, pathogenesis of autoimmune disease and carcinogenesis. In light of the directly down-regulation of miR-152 on DNMT1 expression by targeting the 3' untranslated regions of its transcript in nickel sulfide (NiS)-transformed human bronchial epithelial cells, we investigated whether miR-152 is aberrantly expressed and targets DNMT1 in FLS in Arthritic rat model. Our results demonstrated that the expression of miR-152 was specifically down-regulated in Arthritic rat model, whereas up-regulation of miR-152 in FLS resulted in a marked reduction of DNMT1 expression. Further experiments revealed that increased miR-152 indirectly up-regulated the SFRP4 expression, a negative regulator of WNT signaling pathway, by targeting the DNMT1. Moreover, activation of miR-152 expression in FLS could inhibit the canonical Wnt pathway activation and result in a significant decrease of FLS proliferation. MiR-152 and DNA methylation may provide molecular mechanisms for the activation of canonical Wnt pathway in RA. Combination of miR-152 and DNMT1 may be a promising treatment strategy for RA patients in which SFRP4 is inactivated.
authors.affiliation: School of Food and Drug, Anhui Key Laboratory of Poultry Epidemic Prevention and Surveillance, Anhui Science and Technology University, Bengbu 233100, China; School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.
authors.forename: Cheng-Gui
authors.initials: CG
authors.lastname: Miao
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Yang
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.
authors.forename: Xu
authors.initials: X
authors.lastname: He
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: School of Food and Drug, Anhui Key Laboratory of Poultry Epidemic Prevention and Surveillance, Anhui Science and Technology University, Bengbu 233100, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Qin
authors.affiliation: School of Food and Drug, Anhui Key Laboratory of Poultry Epidemic Prevention and Surveillance, Anhui Science and Technology University, Bengbu 233100, China.
authors.forename: Chuan-Lai
authors.initials: CL
authors.lastname: Du
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China. Electronic address: lijunamu@126.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D015151:Immunoblotting; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; C578788:MIRN152 microRNA, rat; C498455:Sfrp4 protein, rat; D000094742:Secreted Frizzled-Related Proteins; C000619380:DNMT1 protein, human; C000619382:Dnmt1 protein, rat
keywords: Canonical Wnt pathway; DNA methyltransferase 1; MicroRNA-152; Rheumatoid arthritis; Secreted frizzled-related protein 4