Academic Unit of Rheumatology, Department of Infection and Immunity, The Medical School, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK.
Biochem Soc Trans. 2013 Jun;41(3):783-8. doi: 10.1042/BST20130053.
RA (rheumatoid arthritis) is an inflammatory disease of synovial joints affecting approximately 1% of the population. One of the main cell types involved in damage to RA joint tissue is the FLSs (fibroblast-like synoviocytes). These have a semi-transformed, auto-aggressive phenotype typified by loss of contact inhibition, reduced apoptosis and the production of matrix-degrading enzymes. The mechanisms involved in the development of this phenotype are unclear; however, increasing evidence implicates alterations in the epigenetic regulation of gene expression. Reduced acetylation of amino acids in the tails of histone proteins is an epigenetic mark associated with transcriptional repression and is controlled by the HDAC (histone deacetylase) enzyme family. To date, evidence has implicated HDACs in the auto-aggressive phenotype of FLSs, and administration of HDAC inhibitors to both animal models of RA and individuals with juvenile arthritis has shown efficacy in attenuating inflammation and tissue damage. This highlights a role for HDACs in disease pathogenesis and, more importantly, that HDACs are potential novel therapeutic targets.
类风湿关节炎（RA）是一种影响滑膜关节的炎症性疾病，大约影响 1%的人群。RA 关节组织损伤中涉及的主要细胞类型之一是成纤维样滑膜细胞（FLSs）。这些细胞表现出半转化、自体攻击性表型，特征为丧失接触抑制、细胞凋亡减少以及基质降解酶的产生。这种表型发展的机制尚不清楚；然而，越来越多的证据表明，基因表达的表观遗传调控发生了改变。组蛋白尾部氨基酸乙酰化程度降低是一种与转录抑制相关的表观遗传标记，由 HDAC（组蛋白去乙酰化酶）酶家族控制。迄今为止，有证据表明 HDACs 参与了 FLSs 的自体攻击性表型，并且在 RA 动物模型和青少年关节炎患者中使用 HDAC 抑制剂显示出在减轻炎症和组织损伤方面的疗效。这突出了 HDACs 在疾病发病机制中的作用，更重要的是，HDACs 是潜在的新型治疗靶点。
