Department of Orthopaedics, The Affiliated Hospital of Southwest Medical University, Sichuan Provincial Laboratory of Orthopaedic Engineering Luzhou, Sichuan, China.
Laboratory Animal Center, Southwest Medical University, Luzhou, Sichuan, China.
Kaohsiung J Med Sci. 2024 Apr;40(4):335-347. doi: 10.1002/kjm2.12805. Epub 2024 Feb 16.
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, and the role of HOXA transcript at the distal tip (HOTTIP) in its pathogenesis remains underexplored. This study investigates the mechanism by which HOTTIP influences apoptosis and the inflammatory response of fibroblast-like synoviocytes (FLS). An RA mouse model was established, and clinical scores were analyzed. Pathological changes in synovial tissues, bone mineral density (BMD) of the paws, serum tartrate-resistant acid phosphatase (TRAP) activity, and TNF-α and IL-1β levels were assessed. FLS were transfected, and cell proliferation and apoptosis were examined. The RNA-pull-down assay determined HOTTIP's interaction with mixed-lineage leukemia 1 (MLL1), while RNA immunoprecipitation assay measured HOTTIP expression pulled down by MLL1. The levels of MLL1 and toll-like receptor 4 (TLR4) after MLL1 overexpression based on HOTTIP silencing were determined. Chromatin immunoprecipitation (ChIP) was performed with H3K4me3 as an antibody, followed by the evaluation of TLR4 expression. HOTTIP expression was elevated in RA mouse synovial tissues. Inhibition of HOTTIP led to reduced clinical scores, inflammatory infiltration, synovial hyperplasia, TRAP activity, and TNF-α and IL-1β levels, along with increased BMD. In vitro Interference with HOTTIP suppressed RA-FLS apoptosis and inflammation. HOTTIP upregulated TLR4 expression by recruiting MLL1 to facilitate TLR4 promoter methylation. MLL1 overexpression reversed HOTTIP silencing-mediated repression of RA-FLS apoptosis. Activation of H3K4 methylation counteracted HOTTIP knockout, ameliorating the inflammatory response. HOTTIP regulates TLR4 expression by recruiting MLL1, leading to TLR4 promoter methylation, thereby suppressing RA-FLS proliferation and inducing cell apoptosis and inflammatory response in RA.
类风湿关节炎（RA）是一种慢性自身免疫性炎症性疾病，HOXA 转录远端末端（HOTTIP）在其发病机制中的作用仍未得到充分探索。本研究探讨了 HOTTIP 影响成纤维样滑膜细胞（FLS）凋亡和炎症反应的机制。建立了 RA 小鼠模型，并分析了临床评分。评估滑膜组织的病理变化、爪子的骨矿物质密度（BMD）、血清抗酒石酸酸性磷酸酶（TRAP）活性以及 TNF-α 和 IL-1β 水平。转染 FLS，并检查细胞增殖和凋亡。RNA 下拉实验确定了 HOTTIP 与混合谱系白血病 1（MLL1）的相互作用，而 RNA 免疫沉淀实验则测量了 MLL1 下拉的 HOTTIP 表达。根据 HOTTIP 沉默，确定 MLL1 过表达后 MLL1 和 Toll 样受体 4（TLR4）的水平。用 H3K4me3 作为抗体进行染色质免疫沉淀（ChIP），然后评估 TLR4 的表达。在 RA 小鼠滑膜组织中 HOTTIP 表达上调。抑制 HOTTIP 导致临床评分降低、炎症浸润、滑膜增生、TRAP 活性以及 TNF-α 和 IL-1β 水平降低，同时 BMD 增加。体外干扰 HOTTIP 抑制 RA-FLS 凋亡和炎症。HOTTIP 通过招募 MLL1 上调 TLR4 表达，促进 TLR4 启动子甲基化。MLL1 过表达逆转了 HOTTIP 沉默介导的对 RA-FLS 凋亡的抑制。H3K4 甲基化的激活抵消了 HOTTIP 敲除，改善了炎症反应。HOTTIP 通过招募 MLL1 调节 TLR4 表达，导致 TLR4 启动子甲基化，从而抑制 RA-FLS 的增殖，并在 RA 中诱导细胞凋亡和炎症反应。
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