Journal Article

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

Lee, In-Hyun, Lee, Kwang Min, Choi, Somang, Ok, Subin, Yang, Siyoung, Son, Min-Hee, Lee, Hyemi, Choi, Seungseok, Yoon, Injoo, Ryu, Serim, Han, Seong Jae, Kim, Jina, Cho, Chanmi

2025

Overview

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 in vitro and in vivo models. In vitro , 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. In vivo , 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.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Acetamides - chemistry / Acetamides - therapeutic use / Animal models / Animals / arthritis / bromodomain / Bromodomain Containing Proteins - antagonists & inhibitors / Bromodomain Containing Proteins - genetics / Bromodomain Containing Proteins - immunology / carboxamide derivative / Cartilage / Cartilage diseases / Cells, Cultured / Chondrocytes / Chondrocytes - drug effects / Chondrocytes - immunology / Collagenase 3 / Cyclooxygenase-2 / Dehydrogenases / Disease Models, Animal / Epigenesis, Genetic / Epigenetics / Gene expression / IL-1β / Immunology / Inflammation / Kinases / Laboratory animals / Ligands / Male / MAP kinase / Matrix metalloproteinase / Medical research / Meniscus / Mice / Mice, Inbred C57BL / mitogen-activated protein kinase / Mitogen-Activated Protein Kinases - metabolism / NF-kappa B - metabolism / NF-κB / NF-κB protein / Oral administration / Osteoarthritis / Osteoarthritis - drug therapy / Osteoarthritis - genetics / Osteoarthritis - immunology / Osteoarthritis - pathology / Pathogenesis / Phosphorylation / Polymerase chain reaction / Proteins / Reverse transcription / Sensors / Signal transduction / Signal Transduction - drug effects / Stromelysin 1 / Therapeutic targets / Toxicity / Transcription Factors - antagonists & inhibitors / Transcription Factors - genetics / Transcription Factors - immunology / Western blotting