MicroRNA-152 modulates the canonical Wnt pathway activation by targeting DNA methyltransferase 1 in arthritic rat model

• Published in: Biochimie 2014-11, Vol.106, p.149-156
• Main Authors: Miao, Cheng-gui, Yang, Ying-ying, He, Xu, Huang, Cheng, Huang, Yan, Qin, Dan, Du, Chuan-lai, Li, Jun
• Format: Article
• Language: English
• Subjects: Animals; Arthritis, Experimental - genetics; Arthritis, Experimental - metabolism; Canonical Wnt pathway; Cell Proliferation - genetics; Cells, Cultured; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA methyltransferase 1; Gene Expression Regulation; Humans; Immunoblotting; Male; MicroRNA-152; MicroRNAs - genetics; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Rheumatoid arthritis; Secreted frizzled-related protein 4; Synovial Membrane - cytology; Synovial Membrane - metabolism; Wnt Signaling Pathway - genetics
• ISSN: 0300-9084; 1638-6183
• DOI: 10.1016/j.biochi.2014.08.016

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. •MiR-152 is specifically down-regulated in RA rats compared with controls.•Increased miR-152 in FLS results in a marked reduction of DNMT1 expression.•MiR-152 indirectly up-regulates the SFRP4 expression by targeting DNMT1.•MiR-152 inhibits the canonical Wnt pathway activation and FLS proliferation.