Procyanidin C1 ameliorates osteoarthritis through epigenetic modulation of RAGEs.

Procyanidin C1 (PC1), a dietary bioactive compound derived from fruits and food, exhibits potent antioxidant activity. The upregulation of the receptor for advanced glycation end products (RAGEs) is closely associated with osteoarthritis (OA) pathogenesis. In this study, we identified PC1 as a potential epigenetic suppressor of RAGE expression, revealing its protective bioactivity against OA. Specifically, we observed a dose-dependent decrease of RAGE expression upon PC1 treatment in the chondrocyte cell line. Similarly, PC1 suppressed RAGEs in human primary OA chondrocytes, resulting in reduced ROS production and attenuated NF-κB activity. PC1 improved the osteoarthritic microenvironment and energetic metabolism, as evidenced by increased chondrogenic markers and decreased inflammatory markers, and the rebalance of mitochondrial respiration and the glycolytic level. Meanwhile, PC1 also suppressed OA chondrocyte apoptosis and promoted autophagy. Correspondingly, PC1-mediated beneficial improvements of OA were abrogated by RAGE overexpression. Mechanistic studies revealed PC1 modulated RAGE expression by promoting hypermethylation of the RAGE promoter. To validate this epigenetic regulation, dCAS9-TET1 targeting the RAGE promoter was employed to counteract PC1-driven epigenetic modification, which blocked PC1-induced hypermethylation and the RAGE level was also restored. Collectively, this study provides a mechanistic basis for the use of PC1-rich foods as a potential strategy for nutritional intervention against OA.