Betulin inhibits inflammatory factors synthesis in osteoarthritis synovial fibroblasts by suppressing the PI3K, Akt, and mTOR pathways and activating miR-5006-5p

Osteoarthritis (OA) is a widespread joint condition often linked to aging and obesity, resulting in pain, joint dysfunction, and disability. Betulin, a lupane-type pentacyclic triterpene alcohol extracted from birch trees, exhibits anti-inflammatory properties; however, its anti-inflammatory effects in OA remain largely unknown. Our high-throughput cytokine array data exhibit that betulin inhibits two key inflammatory factors, CHI3L1 and ICAM-1, in OA synovial fibroblasts (OASFs). Results from the GEO database and our clinical tissues confirm that CHI3L1 and ICAM-1 levels are markedly higher in OA patients compared to healthy individuals. Furthermore, anterior cruciate ligament transection (ACLT)-induced OA rats exhibited upregulated CHI3L1 and ICAM-1 expression. Mechanistically, we demonstrated that betulin inhibits CHI3L1 and ICAM-1 synthesis in OASFs by inhibiting the PI3K, Akt, and mTOR pathways and activating miR-5006-5p. Importantly, molecular docking analysis predicted an interaction between betulin with CHI3L1 and ICAM-1, suggesting its direct effects. Our investigation suggests that betulin is a leading candidate for OA management.