Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction. Cell-derived small extracellular vesicles (sEV) mediate cell-to-cell communication in the synovial microenvironment by carrying microRNAs (miRs), a class of small non-coding RNAs. Herein, we report that sEV from synovial fluid promote osteoclast differentiation which is attributed to high levels of extracellular miR-574-5p. Moreover, we demonstrate for the first time that enhanced osteoclast maturation is mediated by Toll-like receptor (TLR) 7/8 signaling which is activated by miR-574-5p binding. This is a novel mechanism by which sEV and miRs contribute to RA pathogenesis and indicate that pharmacological inhibition of extracellular miR-574-5p might offer new therapeutic strategies to protect osteoclast-mediated bone destruction in RA.
Highlights
Rheumatoid arthritis (RA) is one of the most common systemic autoimmune diseases, characterized by synovial inflammation and the destruction of cartilage and bone [1]
We investigated whether small extracellular vesicles (sEV) isolated from the synovial fluid of ACPA+ RA patients influence osteoclastogenesis
A similar increase was observed, when macrophages, a later stage of OC differentiation, were treated with sEV (Figure 1E). These results suggest that the content of sEV derived from the synovial fluid of RA patients may contribute to an increased OC differentiation process
Summary
Rheumatoid arthritis (RA) is one of the most common systemic autoimmune diseases, characterized by synovial inflammation and the destruction of cartilage and bone [1]. The synovial fluid of affected joints contain high amounts of extracellular vesicles (EV) [5]. These are membrane vesicles of endocytic origin that are actively secreted by almost all cell types into biofluids [6] and may play an important role in the pathogenesis of RA [7]. A subpopulation of EV, termed small extracellular vesicles (sEV, 50–200 nm in diameter) [8], are involved in cell-to-cell communication in the microenvironment of arthritic joints [9]. Among other biologically active substances, sEV contain microRNAs (miRs), a class of small non-coding RNAs [10]. An alternative function of extracellular miRs has been described, based on their ability to induce innate immune responses
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