Division of Rheumatology, Allergy and Immunology, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.
PLoS One. 2024 Jun 3;19(6):e0304530. doi: 10.1371/journal.pone.0304530. eCollection 2024.
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.
类风湿关节炎（RA）是一种系统性免疫介导的疾病，其特征为关节炎症和破坏。该疾病通常影响手和脚的小关节，随后进展为累及膝关节、肩关节和髋关节等更大的关节。尽管这些关节特异性差异的原因尚不清楚，但已报道与关节位置相关的独特表观遗传模式。在这项研究中，我们评估了 RA 患者来自髋关节和膝关节滑膜的成纤维样滑膜细胞（FLS）的独特表观遗传景观，重点关注同源盒（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着关键作用，并且已知在各种成人组织中维持着独特的表达模式。我们发现，与髋关节 FLS 相比，膝关节 FLS 中几个 HOX 基因，特别是 HOXD10，表达存在差异。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。组蛋白修饰，特别是组蛋白乙酰化，被确定为 HOXD10 表达的重要调节剂。为了了解差异表达 HOXD10 的机制，我们用小分子和 siRNA 抑制组蛋白去乙酰化酶（HDACs）。我们发现，HDAC1 阻断或缺乏可使关节特异性 HOXD10 表达模式正常化。这些观察结果表明，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 表达中起着关键作用。了解这些机制可能为 RA 的区域性方面提供深入了解，并可能导致针对疾病过程中特定关节受累模式的治疗策略。
