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Background <p>Osteoarthritis ranks as the most prevalent orthopedic disease and the knee is one of the commonly affected joints. Osthole is a natural coumarin that has been shown to reduce cartilage degeneration. This study sought to elucidate whether osthole reduces cartilage damage in knee osteoarthritis (KOA) and its mechanism of action.</p> Methods <p>From the knee joints of SD rats, chondrocytes were obtained and subsequently identified by light microscopy, Alcian blue staining, immunofluorescence, and toluidine blue staining. The impact of osthole on the viability of normal chondrocytes as well as interleukin (IL)-1β-treated chondrocytes was examined through a Cell Counting Kit-8 assay to screen for appropriate treatment concentrations. Chondrocyte apoptosis was detected through flow cytometry and TUNEL staining, and endoplasmic reticulum stress (ERS) marker protein expression was detected by immunofluorescence. A KOA rat model was constructed by injecting sodium iodoacetate and evaluated by pathological staining for articular cartilage damage in rat knee bones. ELISA kits detected inflammatory cytokines in chondrocytes and rat serum. Western blot detected the expression levels of apoptosis, ERS, extracellular matrix (ECM), inflammatory factors, and HMGB1/RAGE/NF-κB pathway-related proteins.</p> Results <p>Osthole (50, 75, and 100&#xa0;μmol/L) had no adverse effect on chondrocyte viability and was able to increase chondrocyte viability, inhibit apoptosis, and suppress the abnormal expression of ECM-related proteins after IL-1β treatment. Osthole effectively reduced inflammatory factor levels in chondrocytes and rat serum, downregulated ERS-related proteins, and alleviated the pathological damage of cartilage tissue in KOA rats. Notably, ERS agonists attenuated the suppressive impacts of osthole on chondrocyte apoptosis and ECM degeneration. Furthermore, osthole hindered the HMGB1/RAGE/NF-κB pathway, whereas overexpression of HMGB1 impaired the suppressive impacts of osthole on chondrocyte apoptosis, inflammation, and ERS.</p> Conclusion <p>Osthole inhibits chondrocyte inflammation, apoptosis, and ERS, and alleviates cartilage histopathological damage through inhibiting the HMGB1/RAGE/NF-κB pathway.</p> Graphical abstract <p>Osthole inhibited the HMGB1/RAGE/NF-κB pathway, thereby alleviating chondrocyte inflammation, apoptosis, and extracellular matrix degeneration caused by IL-1β, and ameliorating cartilage tissue damage and suppressing cartilage inflammation and endoplasmic reticulum stress in KOA rats.</p>

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Osthole protects against cartilage damage in knee osteoarthritis rats by attenuating inflammation and endoplasmic reticulum stress through the HMGB1/RAGE/NF-κB pathway

  • 期刊论文

  • 发表日期：

    2026年4月26日

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  • Feng Zhou,
  • Yangcheng Liu,
  • Jianlong Zhu,
  • Feng Yang,
  • Zhongning Guan,
  • Zhijiang Jin,
  • Hongchang Zhao,
  • Lifeng Pan

摘要

Background

Osteoarthritis ranks as the most prevalent orthopedic disease and the knee is one of the commonly affected joints. Osthole is a natural coumarin that has been shown to reduce cartilage degeneration. This study sought to elucidate whether osthole reduces cartilage damage in knee osteoarthritis (KOA) and its mechanism of action.

Methods

From the knee joints of SD rats, chondrocytes were obtained and subsequently identified by light microscopy, Alcian blue staining, immunofluorescence, and toluidine blue staining. The impact of osthole on the viability of normal chondrocytes as well as interleukin (IL)-1β-treated chondrocytes was examined through a Cell Counting Kit-8 assay to screen for appropriate treatment concentrations. Chondrocyte apoptosis was detected through flow cytometry and TUNEL staining, and endoplasmic reticulum stress (ERS) marker protein expression was detected by immunofluorescence. A KOA rat model was constructed by injecting sodium iodoacetate and evaluated by pathological staining for articular cartilage damage in rat knee bones. ELISA kits detected inflammatory cytokines in chondrocytes and rat serum. Western blot detected the expression levels of apoptosis, ERS, extracellular matrix (ECM), inflammatory factors, and HMGB1/RAGE/NF-κB pathway-related proteins.

Results

Osthole (50, 75, and 100 μmol/L) had no adverse effect on chondrocyte viability and was able to increase chondrocyte viability, inhibit apoptosis, and suppress the abnormal expression of ECM-related proteins after IL-1β treatment. Osthole effectively reduced inflammatory factor levels in chondrocytes and rat serum, downregulated ERS-related proteins, and alleviated the pathological damage of cartilage tissue in KOA rats. Notably, ERS agonists attenuated the suppressive impacts of osthole on chondrocyte apoptosis and ECM degeneration. Furthermore, osthole hindered the HMGB1/RAGE/NF-κB pathway, whereas overexpression of HMGB1 impaired the suppressive impacts of osthole on chondrocyte apoptosis, inflammation, and ERS.

Conclusion

Osthole inhibits chondrocyte inflammation, apoptosis, and ERS, and alleviates cartilage histopathological damage through inhibiting the HMGB1/RAGE/NF-κB pathway.

Graphical abstract

Osthole inhibited the HMGB1/RAGE/NF-κB pathway, thereby alleviating chondrocyte inflammation, apoptosis, and extracellular matrix degeneration caused by IL-1β, and ameliorating cartilage tissue damage and suppressing cartilage inflammation and endoplasmic reticulum stress in KOA rats.