Predisposal of Interferon Regulatory Factor 1 Deficiency to Accumulate DNA Damage and Promote Osteoarthritis Development in Cartilage

Abstract

ObjectiveInterferon 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.MethodsOA 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.ResultsOur 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.ConclusionIRF1 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