Osteoarthritis (OA) is an age-related degenerative disease for which an effective disease-modifying therapy is not available. Natural compounds derived from plants have been traditionally used in the clinic to treat OA. Over the years, many studies have explored the treatment of OA using natural extracts. Although various active natural extracts with broad application prospects have been discovered, single compounds are more important for clinical trials than total natural extracts. Moreover, although natural extracts exhibit minimal safety issues, the cytotoxicity and function of all single compounds in a total extract remain unclear. Therefore, understanding single compounds with the ability to inhibit catabolic factor expression is essential for developing therapeutic agents for OA. This review describes effective single compounds recently obtained from natural extracts and the possibility of developing therapeutic agents against OA using these compounds.

Background and Purpose: The discovery of new bromo‐ and extra‐terminal inhibitors presents new drugs to treat osteoarthritis (OA).Experimental Approach: The new drug, BBC0403, was identified in the DNA‐encoded library screening system by searching for compounds that target BRD (bromodomain‐containing) proteins. The binding force with BRD proteins was evaluated using time‐resolved fluorescence energy transfer (TR‐FRET) and binding kinetics assays. Subsequently, in vitro and ex vivo analyses demonstrated the effects of the BRD2 inhibitor, BBC0403, on OA. For animal experiments, medial meniscus destabilization was performed to create a 12‐week‐old male C57BL/6 mouse model, and intra‐articular (i.a.) injections were administered. Histological and immunohistochemical analyses were then performed. The underlying mechanism was confirmed by gene set enrichment analysis (GSEA) using RNA‐seq.Key Results: TR‐FRET and binding kinetics assays revealed that BBC0403 exhibited higher binding specificity for BRD2 compared to BRD3 and BRD4. The anti‐OA effects of BBC0403 were tested at concentrations of 5, 10 and 20 μM (no cell toxicity in the range tested). The expression of catabolic factors, prostaglandin E2 (PGE₂) production and extracellular matrix (ECM) degradation was reduced. Additionally, the i.a. injection of BBC0403 prevented OA cartilage degradation in mice. Finally, BBC0403 was demonstrated to suppress NF‐κB and MAPK signalling pathways.Conclusion and Implications: This study demonstrated that BBC0403 is a novel BRD2‐specific inhibitor and a potential i.a.‐injectable therapeutic agent to treat OA.