Purpose

Osteoarthritis (OA) is the most prevalent degenerative disease in musculoskeletal system. However, no convincing disease-modifying OA drugs (DMOADs) have received regulatory approval, suggesting that none have convincingly disease-modifying efficacy. Intact cartilage ECM was essential to maintain cartilage function. Thus, modulating cartilage ECM generation represented as a promising approach to treat OA.

Methods and Materials

In the present study, we screened for 2320 compounds using chondrogenesis induction system of ATDC5. We then evaluated the protective effects of compound using OA chondrocyte, OA cartilage explants, and rat OA model developed by ACLT. The molecular target of compound was tested through the experiments in vitro, such as RNA sequencing, RT-PCR, and immunofluorescence analysis et al.

Results

Here we describe BNTA, a small molecule with ECM modulatory properties. BNTA promotes generation of ECM components in cultured chondrocytes isolated from individuals with osteoarthritis. In human osteoarthritic cartilage explants, BNTA treatment stimulates expression of ECM components while suppressing inflammatory mediators. Intra-articular injection of BNTA delays the disease progression in a trauma-induced rat model of osteoarthritis. Furthermore, we identify superoxide dismutase 3 (SOD3) as a mediator of BNTA activity. BNTA induces SOD3 expression and superoxide anion elimination in osteoarthritic chondrocyte culture, and ectopic SOD3 expression recapitulates the effect of BNTA on ECM biosynthesis.

Conclusion

(1) In this study, we reported a novel candidate of DMOAD, BNTA, which significantly enhanced anabolic metabolism in OA chondrocytes, and rescued the decrease of main ECM structural molecules in OA cartilage explants and OA cartilage tissue developed by ACLT in rats.

(2) It was confirmed that BNTA exerted its effect by upregulation of SOD3, which protected chondrocytes by catalyzing the dismutation reaction of superoxide anions.

(3) Upregulation of SOD3 by BNTA or SOD3 plasmid prominently enhanced the anabolism of OA chondrocytes and regulated cartilage ECM synthesis, which identified SOD3 as a promising new drug target for OA.