TNF ‐α Promotes Synovial Inflammation and Cartilage Bone Destruction in Rheumatoid Arthritis via NF ‐ κB / YY1 / miR ‐103a‐3p Axis

ABSTRACT Tumor necrosis factor alpha ( TNF ‐α) plays important roles in inflammation and bone destruction in rheumatoid arthritis ( RA ), but the detailed mechanism is still not fully elucidated. Here, we found that the levels of microRNA ( miR )‐103a‐3p were decreased markedly in the inflamed synovial tissues of patients with RA compared with osteoarthritis ( OA ) or healthy control subjects. Further studies uncovered that miR ‐103a‐3p was significantly downregulated by TNF ‐α/ IL ‐1β in RA fibroblast‐like synoviocytes ( FLSs ) through an NF ‐ κB –dependent manner via the de novo produced transcription factor Yin Yang 1 ( YY1 ). In addition, downregulation of miR ‐103a‐3p in FLSs promoted NF ‐ κB signaling pathway activation, inflammatory cytokines secretion, and bone marrow‐derived monocytes ( BMMs) cells differentiation into osteoclasts, whereas ectopic expression of miR ‐103a‐3p had the opposite effects. Notably, miR ‐103a‐3p was downregulated thousands of times in the sera of RA patients and CIA mice, while the blockade of TNF ‐α with infliximab greatly recovered its levels in RA patients in sustained remission. Consistently, rescue of miR ‐103a‐3p expression by an agomiR potently ameliorated inflammatory responses and bone erosion in CIA mice. Mechanistically, mitogen‐activated protein kinase kinase kinase 7 ( MAP3K7 ) and Dickkopf‐related protein 1 ( DKK1 ) were identified as the direct targets of miR ‐103a‐3p, by which it exerts the effects on synovial inflammation and cartilage bone destruction. Taken together, miR ‐103a‐3p mediates TNF ‐triggered synovial inflammation and joint bone destruction via targeting MAP3K7 and DKK1 ; it thus serves as a candidate target for RA treatment.