内部收益率1
衰老
软骨细胞
DNA损伤
生物
细胞生物学
DNA修复
氧化应激
软骨
基因
遗传学
DNA
基因表达
生物化学
解剖
作者
Yong-Sik Cho,Hyeonkyeong Kim,Geunho Yook,Sangmin Yong,Soy Kim,Mi Kyung Lee,Y J Kim,Jin‐Hee Kim,Tae Woo Kim,Moon Jong Chang,Kyoung Min Lee,Chong Bum Chang,Soon Beom Kang,Jin Hong Kim
摘要
Objective 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 physiological significance of this non‐canonical function remains unexplored. Here, we investigated IRF1's role in osteoarthritis (OA), a condition marked by senescence and chronic joint inflammation. Methods OA progression was examined in wild‐type and Irf1 ‐/‐ mice using histological assessments and micro‐computed tomography (μCT) analysis of whole‐joint OA manifestations, and behavioral assessments of joint pain. An integrated analysis of ATAC‐seq 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 β‐galactosidase (SA‐β‐Gal) activity. Results 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 downregulated in the cartilage of human and mouse OA. While 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. Conclusion 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. image
科研通智能强力驱动
Strongly Powered by AbleSci AI