Abstract
Erosive destruction of joint structures is a critical event in the progression of rheumatoid arthritis (RA), in which fibroblast-like synoviocytes (FLS) are the primary effectors. We previously reported that the ability of RA FLS to degrade extracellular matrix (ECM) components depends on the formation of actin-rich membrane protrusions, called invadosomes, through processes that remain elusive. 14-3-3η belongs to a family of scaffolding proteins involved in a wide range of cellular functions, and its expression is closely related to joint damage and disease activity in RA patients. In this study, we sought to assess the role of 14-3-3η in joint damage by examining its contribution to the invadosome formation phenotype of FLS. Using human primary FLS, we show that 14-3-3η expression is closely associated with their ability to form invadosomes. Furthermore, knockdown of 14-3-3η using shRNAs decreases the level of invadosome formation in RA FLS, whereas addition of the recombinant protein to FLS from healthy individuals promotes their formation. Mechanistic studies suggest that 14-3-3η regulates invadosome formation by increasing Snail expression, a mechanism that involves nuclear exclusion of the transcription repressor FOXO3. Our results implicate the 14-3-3η–FOXO3–Snail axis in promoting the aggressive ECM-degrading phenotype of RA FLS, and suggest a role for this scaffolding protein in cartilage degradation.
Highlights
Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation with progressive destruction of articular cartilage and bone, resulting in pain, functional disability, and premature death
Gene expression analysis of 14-3-3η in primary cultures of fibroblast-like synoviocytes (FLS) indicated that 14-3-3η mRNA levels were significantly increased in FLS from RA patients when compared to synoviocytes from healthy individuals (H FLS) (Figure 1C)
extracellular matrix (ECM) degradation and subsequent joint damage was previously shown to be mediated by invadosome structures formed by RA FLS [19,20]
Summary
Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation with progressive destruction of articular cartilage and bone, resulting in pain, functional disability, and premature death. The levels of 14-3-3η detected were up to fivefold higher in synovial fluid than in the corresponding serum, suggesting that hyperplasic synovium is likely the source of this protein [12]. Serum levels of 14-3-3η were significantly higher in patients with radiographic evidence of joint damage, and the addition of 14-3-3η to inflammatory cells promoted the induction of inflammatory transcripts such as metalloproteinase (MMP)-1 and MMP-3. These data highlight a potential link between 14-3-3η and joint destruction in RA patients [4], but important questions remain as to the mechanism(s) by which 14-3-3η might participate in the processes leading to joint destruction
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