Paeoniflorin modulates DL-glyceraldehyde metabolism to promote mitochondrial dynamics homeostasis and ameliorate knee osteoarthritis cartilage degeneration.

Abstract

<p>BACKGROUND: Knee osteoarthritis (KOA) is a common chronic degenerative joint disease, and its primary pathological feature of articular cartilage is degeneration. Paeniflorin, a bioactive terpene glycoside isolated from Paeonia lactiflora, has demonstrated a protective effect on chondrocytes, but its specific mechanism are not well understood. PURPOSE: The study aimed to clarify the molecular mechanism by which paeoniflorin enhances cartilage repair and metabolic functions. METHODS: The effects of paeoniflorin on chondrocyte were evaluated using cell staining (toluidine blue and Alcian blue), flow cytometry, PCR, Western blotting, and immunofluorescence. A destabilization of the medial meniscus (DMM) -induced rat model with KOA was established. Micro-Computed Tomography, histopathological staining, and immunohistochemistry were used to assess cartilage repair and metabolic changes. Additionally, transcriptomic and metabolomic analyses were conducted to evaluate the effects of paeoniflorin on mitochondrial dynamics-related genes and their differential metabolites. Molecular docking experiments were used to verify these targets. RESULTS: The in vitro experiments demonstrated that paeoniflorin markedly enhanced the proliferative activity of chondrocytes, and reduced the apoptosis rate. in vivo experiments, paeoniflorin intervention significantly improved bone volume and structural parameters of the subchondral bone in rats with KOA and facilitated the repair of cartilage damage. Combined transcriptomic and metabolomic analyses revealed that paeoniflorin promoted mitochondrial homeostasis by regulating DL-glyceraldehyde (DLG), thereby improving chondrocyte energy metabolism. Molecular docking, molecular dynamics simulations, and downstream mechanistic study indicated that paeoniflorin regulated the expression of mitochondrial dynamics-related genes by modulating DLG levels, promoting mitochondrial fusion, and inhibiting excessive fission. CONCLUSION: Paeoniflorin effectively ameliorated cartilage degeneration in KOA by modulating the downstream metabolite DLG to promote mitochondrial dynamic homeostasis.</p>