Institute for Basic Science and Seoul National University, Seoul, South Korea, and Liflex Science, Cheongju, South Korea.
Institute for Basic Science and Seoul National University, Seoul, South Korea.
Arthritis Rheumatol. 2024 Jun;76(6):882-893. doi: 10.1002/art.42815. Epub 2024 Mar 4.
Interferon regulatory factor 1 (IRF1) is a transcriptional regulator conventionally associated with immunomodulation. Recent molecular analyses mapping DNA binding sites of IRF1 have suggested its potential function in DNA repair. However, the physiologic significance of this noncanonical function remains unexplored. Here, we investigated the role of IRF1 in osteoarthritis (OA), a condition marked by senescence and chronic joint inflammation.
OA progression was examined in wild-type and Irf1 mice using histologic assessments and microcomputed tomography analysis of whole-joint OA manifestations and behavioral assessments of joint pain. An integrated analysis of assay for transposase-accessible chromatin with sequencing and whole transcriptome data was conducted for the functional assessment of IRF1 in chondrocytes. The role of IRF1 in DNA repair and senescence was investigated by assaying γ-H2AX foci and senescence-associated beta-galactosidase activity.
Our genome-wide investigation of IRF1 footprinting in chondrocytes revealed its primary occupancies in the promoters of DNA repair genes without noticeable footprint patterns in those of interferon-responsive genes. Chondrocytes lacking IRF1 accumulated irreversible DNA damage under oxidative stress, facilitating their entry into cellular senescence. IRF1 was down-regulated in the cartilage of human and mouse OA. Although IRF1 overexpression did not elicit an inflammatory response in joints or affect OA development, genetic deletion of Irf1 caused enhanced chondrocyte senescence and exacerbated post-traumatic OA in mice.
IRF1 offers DNA damage surveillance in chondrocytes, protecting them from oxidative stress associated with OA risk factors. Our study provides a crucial and cautionary perspective that compromising IRF1 activity renders chondrocytes vulnerable to cellular senescence and promotes OA development.
干扰素调节因子 1（IRF1）是一种传统上与免疫调节相关的转录调节剂。最近对 IRF1 结合 DNA 位点进行的分子分析表明，其在 DNA 修复中具有潜在功能。然而，这种非典型功能的生理意义仍未得到探索。在这里，我们研究了 IRF1 在骨关节炎（OA）中的作用，OA 是一种以衰老和慢性关节炎症为特征的疾病。
通过组织学评估和全关节 OA 表现的微计算机断层扫描分析以及关节疼痛行为评估，在野生型和 Irf1 小鼠中检查 OA 进展。对染色质可及性分析与测序和全转录组数据的综合分析，对软骨细胞中 IRF1 的功能进行了评估。通过检测γ-H2AX 焦点和衰老相关的β-半乳糖苷酶活性，研究了 IRF1 在 DNA 修复和衰老中的作用。
我们对软骨细胞中 IRF1 足迹的全基因组研究表明，它主要占据 DNA 修复基因的启动子，而干扰素反应基因的足迹模式不明显。在氧化应激下，缺乏 IRF1 的软骨细胞积累不可逆转的 DNA 损伤，促进其进入细胞衰老。IRF1 在人骨关节炎和鼠骨关节炎的软骨中均下调。虽然 IRF1 的过表达不会在关节中引起炎症反应或影响 OA 的发展，但 Irf1 的基因缺失会导致软骨细胞衰老加剧，并在小鼠中加剧创伤后 OA。
IRF1 为软骨细胞提供 DNA 损伤监测，保护其免受与 OA 危险因素相关的氧化应激。我们的研究提供了一个重要而谨慎的观点，即削弱 IRF1 的活性会使软骨细胞易受细胞衰老的影响，并促进 OA 的发展。
