Chronic inflammation, synovial hyperplasia, and local hypoxia lead to synovial cell activation
causing severe joint damage in chronic-inflammatory rheumatoid arthritis (RA). The proinflammatory
and joint-destructive property of the increased release of extracellular nucleic acids has
been demonstrated for extracellular mitochondrial DNA and oxidized DNA using an arthritis model.
Microparticles derived from different cells are able to transport nucleic acids to distant cells and promote
cellular activation in RA. In addition, extracellular RNA (eRNA) is present in the RA synovial
lining layer, whereas eDNA could be detected in various areas of synovial tissue when compared to
controls. The main source of eDNA is the formation of neutrophil extracellular traps (NETs) due to increased
amounts of activated neutrophils in the synovial fluid in RA. A central cell type of joint destruction
is the activated RA synovial fibroblast (RASF) characterized by increased production of proinflammatory
factors, matrix-degrading enzymes, enhanced matrix adhesion, and cell migration. eRNA
was shown to be released by RASF under hypoxia and RNase activity was increased in RA synovial
fluid. In vitro, RNase-mediated reduction of eRNA decreased RASF adhesion to cartilage but not proliferation
or adhesion to endothelial cells. In vivo, RNase1 treatment reduced RASF invasion into cartilage.
Therefore, extracellular nucleic acids induced by (auto)immune responses in RA appear to promote
inflammation and local joint destruction.
Keywords: Extracellular RNA, extracellular DNA, toll-like receptors, rheumatoid arthritis, inflammation, autoimmunity, fibroblasts,
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