Inhibition of PARP-1 attenuates osteoarthritis progression by suppressing NF-κB signaling and alleviating chondrocyte senescence.

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by cartilage destruction, inflammation, and chondrocyte senescence, yet no disease-modifying therapies are currently available. Poly(ADP-ribose) polymerase-1 (PARP-1) has been implicated in inflammation and aging, but its role in OA pathogenesis remains incompletely understood. In this study, we investigated the effects of PARP-1 inhibition on OA progression using both in vitro and in vivo rat models. In vitro, rat chondrocytes were stimulated with interleukin-1β (IL-1β) to establish an OA-like phenotype. PARP-1 expression and activity were elevated upon IL-1β stimulation. Inhibition of PARP-1 by specific siRNA significantly reduced the expression of pro-inflammatory mediators (iNOS, COX2) and matrix-degrading enzymes (MMP13, ADAMTS5). PARP-1 inhibition also alleviated IL-1β-induced NAD+ depletion and chondrocyte senescence, as evidenced by decreased p16 expression and SA-β-gal-positive cells, effects that were partially reversed by the SIRT1 inhibitor EX527. Mechanistically, PARP-1 inhibition suppressed IL-1β-induced NF-κB activation by reducing IκB and p65 phosphorylation and inhibiting p65 nuclear translocation. Co-immunoprecipitation experiments revealed a interaction between PARP-1 and IκB. In vivo, intra-articular injection of PARP-1 siRNA in an anterior cruciate ligament transection (ACLT)-induced rat OA model alleviated cartilage degradation, as shown by Safranin O/toluidine blue staining and Mankin scoring. Collectively, these findings demonstrate that PARP-1 inhibition attenuates OA progression by suppressing NF-κB signaling and alleviating chondrocyte senescence, suggesting that PARP-1 represents a potential therapeutic target for OA.