A novel carboxamide bromodomain inhibitor attenuates osteoarthritis via epigenetic repression of NF-κB and MAPK signaling.

Bromodomains are epigenetic readers that modulate gene expression linked to inflammation and cartilage degeneration. Emerging evidence suggests their dysregulation plays a pivotal role in osteoarthritis (OA) pathogenesis, making them promising therapeutic targets. We evaluated the therapeutic efficacy of a novel carboxamide derivative bromodomain inhibitor (NCD) as a potentially safer alternative for preventing OA progression. The inhibitory effects of NCD were assessed through both and models. , mouse primary chondrocytes were stimulated with IL-1β, and the effects of NCD treatment were analyzed using reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. , destabilization of the medial meniscus (DMM) surgery was performed in 12-week-old male C57BL/6 mice, followed by either oral administration or intra-articular (IA) NCD injection. Cartilage integrity was assessed by histology. We analyzed changes in the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways to elucidate the mechanism of NCD. NCD treatment significantly suppressed IL-1β-induced expression of matrix metalloproteinases (Mmp3 and Mmp13) and cyclooxygenase-2 (Cox2) in mouse chondrocytes. In the DMM mouse model, both oral IA administration of NCD alleviated OA-related cartilage destruction. Mechanistically, NCD inhibited IκB degradation and reduced Erk and Jnk phosphorylation, indicating suppression of the NF-κB and MAPK signaling pathways. This study demonstrates that targeting bromodomains with a novel carboxamide-based inhibitor effectively attenuates OA cartilage destruction by suppressing these signaling pathways. These findings support the therapeutic potential of epigenetic modulation in mitigating OA pathogenesis.