IRF1 deficiency predisposes cartilage to accumulate DNA damage and promotes osteoarthritis development

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. 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. 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. 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.