PDF(Pubmed)
Abstract：
Rheumatoid arthritis (RA) is a systemic immune-mediated disease characterized by joint inflammation and destruction. The disease typically affects small joints in the hands and feet, later progressing to involve larger joints such as the knees, shoulders, and hips. While the reasons for these joint-specific differences are unclear, distinct epigenetic patterns associated with joint location have been reported. In this study, we evaluated the unique epigenetic landscapes of fibroblast-like synoviocytes (FLS) from hip and knee synovium in RA patients, focusing on the expression and regulation of Homeobox (HOX) transcription factors. These highly conserved genes play a critical role in embryonic development and are known to maintain distinct expression patterns in various adult tissues. We found that several HOX genes, especially HOXD10, were differentially expressed in knee FLS compared with hip FLS. Epigenetic differences in chromatin accessibility and histone marks were observed in HOXD10 promoter between knee and hip FLS. Histone modification, particularly histone acetylation, was identified as an important regulator of HOXD10 expression. To understand the mechanism of differential HOXD10 expression, we inhibited histone deacetylases (HDACs) with small molecules and siRNA. We found that HDAC1 blockade or deficiency normalized the joint-specific HOXD10 expression patterns. These observations suggest that epigenetic differences, specifically histone acetylation related to increased HDAC1 expression, play a crucial role in joint-specific HOXD10 expression. Understanding these mechanisms could provide insights into the regional aspects of RA and potentially lead to therapeutic strategies targeting specific patterns of joint involvement during the course of disease.
摘要：
类风湿性关节炎（RA）是一种全身性免疫介导的疾病，其特征是关节炎症和破坏。这种疾病通常会影响手和脚的小关节，后来发展到涉及更大的关节，如膝盖，肩膀,和臀部。虽然这些联合特定差异的原因尚不清楚，已经报道了与关节位置相关的不同表观遗传模式。在这项研究中,我们评估了RA患者髋关节和膝关节滑膜成纤维细胞样滑膜细胞（FLS）的独特表观遗传景观，重点研究同源盒(HOX)转录因子的表达和调控。这些高度保守的基因在胚胎发育中起关键作用,并且已知在各种成体组织中维持不同的表达模式。我们发现几个HOX基因,尤其是HOXD10，与髋部FLS相比，在膝关节FLS中差异表达。在膝关节和髋关节FLS之间的HOXD10启动子中观察到染色质可及性和组蛋白标记的表观遗传差异。组蛋白修改,特别是组蛋白乙酰化，被鉴定为HOXD10表达的重要调控因子。为了理解HOXD10差异表达的机制，我们用小分子和siRNA抑制组蛋白脱乙酰酶（HDACs）。我们发现HDAC1阻断或缺乏使关节特异性HOXD10表达模式正常化。这些观察表明，表观遗传差异，特别是与HDAC1表达增加相关的组蛋白乙酰化，在关节特异性HOXD10表达中起关键作用。了解这些机制可以提供对RA的区域方面的见解，并可能导致针对疾病过程中特定关节参与模式的治疗策略。
