IRF2BP2-FOSL2 interaction regulates SOX9-mediated cartilage regeneration in osteoarthritis models

Osteoarthritis (OA) is the most common degenerative joint disease. However, the molecular mechanisms underlying OA-induced cartilage degeneration remain elusive. Here, we identify IFN regulatory factor 2 binding protein 2 (IRF2BP2) as an important regulator of chondrocyte differentiation and articular cartilage regeneration. Irf2bp2 deficiency promoted chondrogenesis and inhibited chondrocyte terminal differentiation by transcriptionally upregulating the key chondrogenic marker SRY-box transcription factor 9 (SOX9), inducing its ectopic expression in the hypertrophic zone. Cartilage-specific KO of Irf2bp2 elevated SOX9 levels, attenuated OA progression in the destabilization of the medial meniscus (DMM) model, and enhanced cartilage regeneration and hyalinization in the microfracture model. Mechanistically, IRF2BP2 bound to and stabilized Fos-related antigen 2 (FOSL2), an activator protein 1 (AP-1) family member, thereby facilitating FOSL2/c-Jun complex formation and repressing SOX9 expression. Adeno-associated virus–mediated (AAV-mediated) FOSL2 overexpression reversed the protective phenotype observed in Irf2bp2 -deficient mice. These findings establish the Hippo/IRF2BP2/FOSL2/SOX9 regulatory axis as critical for cartilage regeneration. Importantly, AAV-mediated IRF2BP2 knockdown, pharmacological targeting of the IRF2BP2/AP-1 axis using T-5224, and delivery of a peptide that disrupts IRF2BP2-FOSL2 binding via intra-articular injection all preserved cartilage integrity, offering potential therapeutic strategies for OA and cartilage regeneration.