Dvl3 Promotes the Phenotypic Transformation of RA-FLS and Aggravation of CIA Through Wnt Pathway by Exosome Intervention.

Abstract ObjectiveThis study was performed to explore the expression pattern of Dvl3 in RA and investigate the function and mechanism of Dvl3 in RA by exosome intervention. Methods: The expression pattern of Dvl3 was examined by IHC, WB, and qPCR. Modified exosomes obtained from culturing supernatant of RA-FLS infected with Dvl3 over expression (OE) lentivirus by ultracentrifugation were administrated to the target RA-FLS. The ability of survival, migration, and the production of inflammatory factor influenced by exosomal Dvl3 were detected by CKK8 kits, Tunel, migration test, qPCR, and enzyme-linked immunosorbent assay (ELISA) respectively; Pathological examination, ELISA, and behave revaluation were performed after injection of exosomes into the articular cavity of CIA mice. The possible downstream pathways of Dvl3 were screened by qPCR and WB, and verified by double luciferase reporter experiment.ResultsThe expression level of Dvl3 was significantly increased in RA and CIA. Exosomes from the OE group could significantly promote cell proliferation activity, migration/invasion ability. The augment of TNF-α, IL-1β, IL-17, and IL-21 was observed in exosomal Dvl3-OE group. The deteriorated role of exosomal Dvl3 in collagen-induced arthritis model (CIA) has been fully demonstrated in terms of cartilage destruction, apoptosis, and inflammation. Over expression of Dvl3 was accompanied by the significant increase of β-catenin and RhoA activities.ConclusionThis study discovered the high expression of Dvl3 of exosomes derived from RA patients which may possessed the ability to promote phenotypic transformation of RA-FLS and aggravation of CIA through Wnt pathway.