School of pharmacy, Anhui key laboratory of bioactivity of natural products, Anhui Medical University, Hefei 230032, China.
Cell Signal. 2013 Mar;25(3):598-608. doi: 10.1016/j.cellsig.2012.11.023. Epub 2012 Nov 29.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by the rheumatoid factor and anti-citrullinated peptide antibody (ACPA) against common autoantigens that are widely expressed within and outside the joints. Many factors participate in the pathogenesis of RA, such as cytokine imbalance, Wnt pathway activation, matrix production, and osteoprotegerin on osteoclasts. Fibroblast-like synoviocytes (FLS) activation has an important role in RA pathogenesis. The methyl-CpG-binding protein (MeCP2) which promoted repressed chromatin structure was selectively detected in synovium of diseased articular in rats. Overexpression of this protein results in an up-regulation of global methylation levels and transcriptional suppression of specific genes. There were increased MeCP2 and decreased secreted frizzled-related protein 4 (SFRP4) in synovium as well as the FLS isolated from the synovium of RA rats. Knockdown of MeCP2 using siRNA technique enhanced SFRP4 expression in both mRNA and protein levels in FLS. These results indicated that epigenetic modification was involved in differential expression of SFRP4. To further explore the underlying molecular mechanisms, we hypothesized that the SFRP4 down-regulation in synovium was caused by DNA methylation. Treatment of FLS with DNA methylation inhibitor 5-Aza-2'-deoxycytidine (5-azadC) blocked the cell proliferation and increased the SFRP4 expression. Increased SFRP4 down-regulated the key gene β-catenin, the downstream effectors gene ccnd1 and fibronectin expression in canonical Wnt pathway at the same time. MeCP2 and DNA methylation may provide molecular mechanisms for canonical Wnt pathway activation in RA. Combination of 5-azadC and MeCP2 may be a promising treatment strategy for individuals with RA in which SFRP4 is inactivated.
类风湿关节炎（RA）是一种自身免疫性疾病，其特征是存在针对关节内外广泛表达的常见自身抗原的类风湿因子和抗瓜氨酸肽抗体（ACPA）。许多因素参与 RA 的发病机制，如细胞因子失衡、Wnt 通路激活、基质产生和破骨细胞上的护骨素。成纤维样滑膜细胞（FLS）的激活在 RA 的发病机制中起着重要作用。在患病关节的滑膜中，选择性检测到促进受抑制染色质结构的甲基-CpG 结合蛋白（MeCP2）。该蛋白的过表达导致整体甲基化水平上调和特定基因的转录抑制。在 RA 大鼠的滑膜以及从滑膜中分离出的 FLS 中，MeCP2 增加，分泌卷曲相关蛋白 4（SFRP4）减少。使用 siRNA 技术敲低 MeCP2 可增强 FLS 中 SFRP4 的 mRNA 和蛋白水平表达。这些结果表明，表观遗传修饰参与了 SFRP4 的差异表达。为了进一步探讨潜在的分子机制，我们假设 SFRP4 在滑膜中的下调是由 DNA 甲基化引起的。用 DNA 甲基化抑制剂 5-氮杂-2'-脱氧胞苷（5-azadC）处理 FLS 可阻断细胞增殖并增加 SFRP4 的表达。同时，增加的 SFRP4 下调了经典 Wnt 通路中的关键基因 β-连环蛋白、下游效应物基因 ccnd1 和纤维连接蛋白的表达。MeCP2 和 DNA 甲基化可能为 RA 中经典 Wnt 通路的激活提供分子机制。5-azadC 和 MeCP2 的联合可能是 SFRP4 失活的 RA 患者的一种有前途的治疗策略。
