Gypenoside XVII Ameliorates Osteoarthritis and Suppresses Chondrocyte Apoptosis and Extracellular Matrix Degradation via STING-Dependent Inhibition of ER Stress.

Excessive activation of endoplasmic reticulum (ER) stress, chondrocyte apoptosis, and extracellular matrix (ECM) degradation are considered critical pathological factors in OA. However, current therapies are not effective enough to mitigate OA progression. Previous studies reported that gypenosides could suppress chondrocyte injury in human osteoarthritis chondrocytes. However, the mechanisms of these therapeutic effects remain largely elusive. In this study, we focused on the investigation of influences and underlying mechanisms of Gypenoside XVII (GP-17), a newly discovered gypenoside monomer extracted from gypenosides in OA. We used tert-butyl hydroperoxide (TBHP) to create an over-accumulation of reactive oxygen species in vitro, mimicking oxidative stress-mediated ER stress in OA. We meticulously analyzed parameters such as chondrocyte apoptosis, synthesis and degradation of ECM, and levels of ER stress. Additionally, the X-ray imaging, Safranin O staining, histopathological analysis, immunohistochemical and immunofluorescent staining were assessed to evaluate the protective effect of GP-17 on cartilage in vivo. Our findings revealed that GP-17 effectively mitigated ER stress created by TBHP, subsequently halting chondrocyte apoptosis, as well as preventing ECM degradation. These outcomes were subsequently validated in an in vivo model of destabilized medial meniscus (DMM)-induced OA in mice. Notably, the PERK-eIF2α-CHOP axis shows heightened sensitivity, being suppressed by GP-17 at lower concentrations (5 and 10 μM). Further studies revealed that the effects of GP-17 are mediated through downregulation of STING. Our results advocate for the potential use of GP-17 as a therapeutic agent in OA treatment.