School of Pharmacy, The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Anhui Medical University, Meishan Road No. 81, Hefei, Anhui Province, 230032, China.
The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Meishan Road No. 81, Hefei, 230032, China.
Inflammation. 2017 Oct;40(5):1497-1508. doi: 10.1007/s10753-017-0591-8.
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, in which pathogenesis is not clear. Many research demonstrated that fibroblast-like synoviocytes (FLSs) play a key role in RA pathogenesis, join in the cartilage injury and hyperplasia of the synovium, and contribute to the release of inflammatory cytokines. We used adjuvant arthritis (AA) rats as RA animal models. The methyl-CpG-binding protein 2 (MeCP2) enables the suppressed chromatin structure to be selectively detected in AA FLSs. Overexpression of this protein leads to an increase of integral methylation levels. Some research has confirmed the hedgehog (Hh) signaling pathway plays an important role in RA pathogenesis; furthermore, patched 1 (PTCH1) is a negative fraction of Hh signaling pathway. We used 5-aza-2'-deoxycytidine (5-azadc) as DNA methylation inhibitor. In our research, we found MeCP2 reduced PTCH1 expression in AA FLSs; 5-azadc obstructed the loss of PTCH1 expression. 5-Azadc, treatment of AA FLSs, also blocks the release of inflammatory cytokines. In order to probe the potential molecular mechanism, we assumed the epigenetic participation in the regulation of PTCH1. Results demonstrated that PTCH1 hypermethylation is related to the persistent FLS activation and inflammation in AA rats. Knockdown of MeCP2 using small-interfering RNA technique added PTCH1 expression in AA FLSs. Our results indicate that DNA methylation may offer molecule mechanisms, and the reduced PTCH1 methylation level could regulate inflammation through knockdown of MeCP2. Graphical Abstract PTCH1 is an inhibitory protein of the Hedgehog signaling pathway. Increased expression of PTCH1 can inhibit the expression of Gli1 and Shh, thereby inhibiting the activation of Hedgehog signaling pathway. Inactivated Hedgehog signaling pathway inhibits the secretion of IL-6 and TNF-α. MeCP2 mediates hypermethylation of PTCH1 gene and decreases the expression of PTCH1 protein, thus activating Hedgehog signaling pathway and increasing secretion of IL-6 and TNF-α.
类风湿关节炎（RA）是一种慢性自身免疫性炎症性疾病，其发病机制尚不清楚。许多研究表明成纤维样滑膜细胞（FLS）在 RA 发病机制中起关键作用，参与软骨损伤和滑膜增生，并有助于炎症细胞因子的释放。我们使用佐剂关节炎（AA）大鼠作为 RA 动物模型。甲基化 CpG 结合蛋白 2（MeCP2）可使 AA FLS 中受抑制的染色质结构被选择性检测到。该蛋白的过表达导致整体甲基化水平升高。一些研究证实 hedgehog（Hh）信号通路在 RA 发病机制中起重要作用；此外，patched 1（PTCH1）是 Hh 信号通路的负分数。我们使用 5-氮杂-2'-脱氧胞苷（5-azadc）作为 DNA 甲基化抑制剂。在我们的研究中，我们发现 MeCP2 降低了 AA FLS 中的 PTCH1 表达；5-azadc 阻止了 PTCH1 表达的丧失。5-azadc 处理 AA FLS 也阻断了炎症细胞因子的释放。为了探究潜在的分子机制，我们假设表观遗传参与了 PTCH1 的调控。结果表明，PTCH1 的高甲基化与 AA 大鼠中 FLS 的持续激活和炎症有关。使用小干扰 RNA 技术敲低 MeCP2 可增加 AA FLS 中的 PTCH1 表达。我们的结果表明，DNA 甲基化可能提供分子机制，降低 PTCH1 的甲基化水平可通过敲低 MeCP2 来调节炎症。
