Fibroblast-like synoviocytes (FLS) can promote joint inflammation and destruction in rheumatoid arthritis (RA) through the production of pro-inflammatory mediators such as IL-15 and dickkopf-related protein 1 (DKK1). New findings published in Arthritis & Rheumatology highlight the involvement of a signalling axis downstream of discoidin domain receptor 2 (DDR2) in this process.

Previous studies had suggested that DDR2, a receptor tyrosine kinase (RTK), is expressed in FLS and contributes to cartilage and bone destruction in RA. In the new study, the researchers found that the expression of DDR2 correlated with the expression of IL-15 and DKK1 both in FLS from patients with RA (RA FLS) and in mice with collagen antibody-induced arthritis (CAIA).

Following collagen antibody treatment, Ddr2−/− mice had milder arthritis than wild-type mice and reduced expression of both IL-15 and DKK1. Restoring the expression of DDR2 in the joints of Ddr2−/− mice using a DDR2-expressing adenovirus increased the arthritis severity score as well as the expression of IL-15 and DKK1.

In vitro experiments in RA FLS identified the long non-coding RNA H19 as a downstream target of the DDR2 signalling cascade. H19 could then interact with and downregulate miR-103a, a microRNA previously shown to be downregulated in RA FLS. Notably, the predicted targets of this microRNA included IL15 and DKK1, and, indeed, data from dual luciferase reporter assays suggested that miR-103a could directly target and repress the expression IL15 and DKK1.

“DDR2 can be blocked by several FDA-approved RTK inhibitors, such as dasatinib and imatinib, and a recent study has shown that inhibition of DDR2 by dasatinib attenuates inflammation severity and bone destruction in mice with CAIA and RA FLS,” explains corresponding author Wei Zhang. Given the low specificity of dasatinib for DDR2, Zhang and colleagues explored the potential of a more recently developed small molecule inhibitor of DDR2, WRG-28.

treatment with WRG-28 was associated with reduced clinical arthritis scores

In the CAIA model, treatment with WRG-28 was associated with reduced clinical arthritis scores, as well as reduced levels of inflammatory cell infiltration and destruction of cartilage and bone. In line with the proposed DDR2–H19–miR-103a signalling axis, WRG-28 treatment was also associated with decreased expression of H19, IL-15 and DKK1 and increased expression of miR-103 in the ankle joints of the mice.