Dysregulated chondrocyte metabolism is an essential risk factor for osteoarthritis (OA) progression. Maintaining cartilage homeostasis represents a promising therapeutic strategy for the treatment of OA. However, no effective disease-modifying therapy is currently available to OA patients. To discover potential novel drugs for OA, we screened a small-molecule natural product drug library and identified deapi-platycodin D3 (D-PDD3), which was subsequently tested for its effect on extracellular matrix (ECM) properties and on OA progression. We found that D-PDD3 promoted the generation of ECM components in cultured chondrocytes and cartilage explants and that intra-articular injection of D-PDD3 delayed disease progression in a trauma-induced mouse model of OA. To uncover the underlying molecular mechanisms supporting these observed functions of D-PDD3, we explored the targets of D-PDD3 via screening approach integrating surface plasmon resonance with liquid chromatography-tandem mass spectrometry. The results suggested that D-PDD3 targeted tyrosine-protein phosphatase non-receptor type 1 (PTP1B), deletion of which restored chondrocyte homeostasis and markedly attenuated destabilization of the medial meniscus induced OA. Further cellular and molecular analyses showed that D-PDD3 maintained cartilage homeostasis by directly binding to PTP1B and consequently suppressing the PKM2/AMPK pathway. These findings demonstrated that D-PDD3 was a potential therapeutic drug for the treatment of OA and that PTP1B served as a protein target for the development of drugs to treat OA. This study provided significant insights into the development of therapeutics for OA treatment, which, in turn, helped to improve the quality of life of OA patients and to reduce the health and economic burden.
Keywords: AMPK; D-PDD3; PTP1B; drug screen; osteoarthritis.
Osteoarthritis is a degenerative disease with a high prevalence and consequently causes a burden to society. However, there is no convincing DMOAD exhibiting effective therapeutic effects on OA. In this study, we screened a small-molecule natural product drug library and identified D-PDD3, which was subsequently tested for its effect on extracellular matrix properties and on OA progression. Further cellular and in vivo experiments showed that D-PDD3 maintains cartilage homeostasis by directly binding to PTP1B and consequently suppressing the PKM2/AMPK pathway. Our results provided fundamental evidence for applying D-PDD3-based therapies against OA, which, in turn, helps to improve the quality of life in OA patients and to reduce the health and economic burden.
© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: [email protected].