Hederagenin binds to monoamine oxidase A to activate chondrocyte autophagy in osteoarthritis therapy.

BACKGROUND

The characteristics of osteoarthritis (OA) is the progressive degeneration of cartilage. Currently, the treatment strategies that can delay or reverse the degeneration of cartilage are still relatively limited. Hederagenin (Hed) is active component of Spatholobus suberectus, has demonstrated multiple pharmacological activities. Investigating the role of Hed in OA treatment may expand interventional approaches for OA.

METHODS

Destabilization of the medial meniscus (DMM) mice model was established, therapeutic effects of Hed on OA mice were evaluated via PCR, histopathological staining and immunohistochemistry. Core target monoamine oxidase A (MAOA) was identified through bioinformatic analyses. Molecular docking, molecular dynamics simulations (MDs), and cellular thermal shift assay (CETSA) were employed to validate the binding stability between Hed and MAOA. WB was performed to evaluate whether Hed modulates autophagy via MAOA bingding in OA intervention.

RESULTS

Phenotypically confirmed the therapeutic effect of Hed in vivo. MAOA expression was downregulated following OA induction, and rescued by Hed treatment. In vitro assays, including molecular docking, MDs, and CETSA, demonstrated stable binding between Hed and MAOA. WB showed that Hed rescued MAOA expression in IL-1β-stimulated primary mouse chondrocytes and promoted the restoration of autophagy flux.

CONCLUSION

We identified MAOA as potential target of Hed in OA intervention. Hed restored the downregulation of MAOA in both in vivo and vitro OA models, and promoted the recovery of autophagic flux. The mechanism might be that Hed binds to MAOA to activate the autophagy-related pathways.