Escin attenuates osteoarthritis via suppressing fibroblast-like synoviocytes Jun-promoted synovial inflammation and osteoclast differentiation.

Abstract

Osteoarthritis (OA) is a chronic, age-related disease that severely impairs the quality of life. The pathogenesis of OA remains unknown, and current pharmacological treatments are still limited. Thus, it is urgent to identify disease targets and develop more effective therapeutic agents for OA. miR-590-3p expression in synovial tissues, fibroblast-like synoviocytes (FLS) and sera of OA patients was detected using miRNA microarray, fluorescence in situ hybridization (FISH), qPCR, and bioinformatics. Luciferase reporter assays and Western blot were employed to confirm the transcriptional regulator of miR-590-3p, proto-oncogene Jun (JUN), and its target genes. Virtual screening, molecular dynamics simulation, and thermal mobility shift assay were performed to screen inhibitors of JUN. The efficacy of escin on OA was verified by constructing a mice model of OA. miR-590-3p was downregulated in the synovium and plasma of OA patients by IL-1β. Mechanistically, OA FLS miR-590-3p expression was regulated by IL-1β/JNK/JUN axis, and was extensively involved in IL-1β-triggered inflammation and osteoclastogenesis through specifically targeting Dickkopf-related protein 1 (DKK1) and receptor activator of nuclear factor-kB Ligand (RANKL). JUN was upregulated in OA synovium and plasma, and located in a hub position of this axis to mediate OA progression. Escin was identified as a targeted inhibitor of JUN, which significantly attenuated OA FLS-mediated inflammation and osteoclast differentiation both in vitro and in vivo via restoring the IL-1β/JUN/miR-590/DKK-1/RANKL axis to normal level. Our study determined that escin inhibits synovial inflammation and bone destruction in OA by directly targeting JUN, leading to the turnover of miR-590-3p and the repression of DKK1 and RANKL. These findings suggest that escin could serve as a promising therapeutic agent for the treatment of OA.