Exosomal miRNA-486-5p derived from rheumatoid arthritis fibroblast-like synoviocytes induces osteoblast differentiation through the Tob1/BMP/Smad pathway

Abstract

The pathogenesis of rheumatoid arthritis (RA) is related to the inhibition of osteoblast differentiation. Exosomes secreted from RA fibroblast-like synoviocytes (RA-FLSs-exos) are associated with the pathogenesis of RA and microRNAs (miRNAs) being crucial for RA progression. Accordingly, the aim of the present study is to elucidate the effect of RA-FLS-derived exosomes on osteoblast differentiation and further identify exosomal cargos responsible for this effect. RA-FLSs were isolated from a RA patient and osteoblasts from the donor bone. Isolated RA-FLSs-exos were co-cultured with osteoblasts. Osteoblast differentiation was evaluated by ALP quantification assays, Alizarin Red S staining, and determining markers of osteoblast activity (Osx, OC, Col1a1 and Dlx2). Collagen induced arthritis (CIA)-induced mouse models were established. RA-FLSs-exo could be phagocytosed by osteoblasts. Elevating the expression of miR-486-5p in RA-FLSs-exo promoted osteoblast differentiation. miR-486-5p targeted Tob1 and activated the BMP/Smad signaling pathway in osteoblasts. In addition, RA-FLSs-exo containing miR-486-5p facilitated osteoblast differentiation by activating the BMP/Smad signaling pathway and repressing Tob1. Moreover, RA-FLSs-exo containing miR-486-5p alleviated the disease severity of RA by decreasing Tob1 expression in CIA-induced mice. To sum up, RA-FLSs-exo carrying miR-486-5p serve as a promoter for osteoblast differentiation in RA, ultimately highlighting a promising competitive new target for RA treatment.