FeiFei Liu,Hao Yang,DongZhe Li,XueJian Wu,QiCai Han
Background Punicalagin (PUN) is a common anti-inflammatory polyphenol. However, the function and mechanism of PUN in osteoarthritis remains unknown. Methods Chondrocytes were isolated from rats, and confirmed by toluidine blue staining and immunofluorescence. Chondrocytes were challenged by lipopolysaccharide (LPS), and rat osteoarthritis model was established by Hulth method. The secretion of inflammatory factors, cell viability and apoptosis were tested via enzyme linked immunosorbent assay (ELISA), MTT and flow cytometry. The levels of forkhead box O1 (Foxo1), proteoglycan 4 (Prg4), hypoxia-inducible factor-3α (HIF3α), autophagy-related genes or extracellular matrix (ECM)-related proteins were examined via quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot or immunohistochemistry . The cartilage tissue damage was assessed via hematoxylin-eosin (HE) staining, toluidine blue staining and terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick and labeling (TUNEL) staining. Results LPS triggered inflammatory injury in chondrocytes. PUN promoted autophagy to mitigate LPS-induced inflammatory injury. Foxo1 silence attenuated the effect of PUN on LPS-mediated autophagy inhibition and inflammatory injury. Promotion of Prg4/HIF3α axis abolished the influence of Foxo1 knockdown on LPS-mediated chondrocytes injury. PUN mitigated the inflammatory injury in rat osteoarthritis model by promoting autophagy and inhibiting inflammation and ECM degradation via Foxo1/Prg4/HIF3α axis. Conclusion PUN attenuates LPS-induced chondrocyte injury and osteoarthritis progression by regulating Foxo1/Prg4/HIF3α axis.
Osteoarthritis (OA) progresses via a destructive cycle involving cartilage damage, friction, lubrication loss, and chondrocyte senescence. Current therapies, limited to temporary lubrication or pain relief, fail to halt OA due to their inability to repair cartilage or restore innate lubrication. To address this challenge, an asymmetric Janus graphene oxide (MGO) nanoplatform is engineered and functionalized with the anti-senescence agent Fenofibrate (FN), creating the MGO-FN system. This integrated design features one side providing robust cartilage adhesion and the opposing side offering superior lubrication, while simultaneously delivering the therapeutic FN. Critically, the nanoscale MGO-FN effectively infiltrates and fills micro-damage on the cartilage surface, enabling localized and sustained FN release. This maximizes drug bioavailability at the target site by minimizing diffusion distances. In vitro, MGO-FN demonstrated potent synergistic effects, significantly enhancing chondrocyte proliferation and extracellular matrix synthesis, reducing senescence, and upregulating the lubrication marker PRG4 more effectively than either component alone. In vivo OA rat studies, supported by transcriptomics analysis, validated MGO-FN's potent therapeutic effects, including reduced cartilage degradation, mitigated inflammation, promoted matrix regeneration, and restored innate lubrication. These findings underscore MGO-FN as a promising multifaceted therapeutic strategy to halt OA progression by concurrently restoring cartilage integrity and lubricating function.
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