Rheumatoid arthritis (RA) is a chronic immune-mediated synovial disease in which fibroblast-like synoviocytes (FLSs) exhibit a tumor-like phenotype that drives cartilage erosion and inflammation. Although MAF BZIP Transcription Factor F (MAFF) has been implicated in RA, its functional role in RA-FLSs remains unclear. MAFF expression was examined in synovial tissues from RA and osteoarthritis (OA) patients using immunohistochemistry, western blotting, and qRT-PCR. Gain- and loss-of-function experiments were performed in primary RA-FLSs and MH7A cells via lentiviral-mediated overexpression or siRNA/shRNA-mediated knockdown. The involvement of NF-κB signaling was evaluated by western blot and by rescue experiments using the NF-κB inhibitor and agonist. The therapeutic potential of MAFF knockdown was evaluated in a mouse model. MAFF expression was significantly upregulated in RA-FLSs. Functional studies revealed that MAFF overexpression enhanced migration, invasion, and IL-6 production in RA-FLSs, while MAFF knockdown suppressed these pathogenic phenotypes. Mechanistically, MAFF activated the NF-κB pathway. MAFF expression was induced by TNF-α stimulation, and MAFF was required for TNF-α-induced NF-κB activation and functional responses. In vivo, intra-articular delivery of MAFF siRNA ameliorated arthritis severity, reduced inflammatory cell infiltration, preserved cartilage integrity, and protected against bone erosion in collagen-induced arthritis mice, effects that were partially reversed by PMA treatment. MAFF is upregulated in RA and functions as a critical downstream mediator of TNF-α-induced NF-κB activation, promoting the aggressive phenotype of RA-FLSs. Targeting MAFF may represent a novel therapeutic strategy for ameliorating joint inflammation and destruction in RA.
Qiu et al. (Mon,) studied this question.