A study published in Annals of the Rheumatic Diseases has identified a function for the tetraspanin CD82 in rheumatoid arthritis (RA). “CD82 at sites of cartilage invasion may reduce RA synovial fibroblast (RASF) motility, keeping them at the site of cartilage destruction,” says corresponding author Elena Neumann.

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CD82 is already well-characterized in tumour cells; by altering cell adhesion CD82 can function as a suppressor of tumour metastasis, preventing the escape of cancer cells from solid tumours. In the new study, the researchers identify a similar function of CD82 in RASFs, but with potential for very different clinical outcomes. Unlike the protective function in tumours, the tethering function of CD82 in the joints might lock RASFs into an inflammatory niche.

…CD82 in the joints might lock RASFs into an inflammatory niche.

Consistent with previous studies, the researchers detected high expression of CD82 in the synovium of patients with RA, with specific localization at the site of inflammation and cartilage invasion and in areas of close proximity to the vasculature.

To test the function of CD82 in this niche, the researchers used either lentiviral overexpression or siRNA knockdown of CD82 in RASFs. Results from cocultures, Boyden chamber and scratch assays show that the more CD82 is expressed by these cells, the less able they are to move around or to uncouple from cell–cell contact with a human endothelial cell monolayer.

Importantly, the paper also shows that pro-inflammatory cytokines induce surface expression of CD82 by RASFs, and that this induction mirrors the effect of CD82 overexpression on cell motility. This finding indicates a vicious cycle of inflammation driven by pro-inflammatory cytokine induction of CD82 that anchors RASFs at the site of inflammation, thus exacerbating joint destruction.

Aside from a potential explanation for the persistence of inflammation in the joint, this finding might open the door to new targeted therapeutic strategies, and Neumann notes that it might also explain some of the therapeutic effects of existing DMARDs.

“The potential to target tetraspanins and to inhibit or modify RASF motility specifically in disease-affected joints would be a highly interesting option,” she adds, “but this is a challenge due to the ubiquitous presence of fibroblasts in almost all connective tissues.”