BackgroundDickkopf related protein 1 (DKK1) has been proposed as the master regulator of joint remodelling. This Wnt signalling pathway inhibitor is involved in osteoblast growth and differentiation. In rheumatoid arthritis, increased DKK1 plasma levels correlate with inflammation and bone erosions. Furthermore, patients with rheumatoid arthritis who carry genetic variants in the DKK1 gene have higher serum DKK1 levels and more progressive joint destruction, suggesting a fundamental role for DKK1 in rheumatoid arthritis. In the diseased joint, synovial fibroblasts are key mediators of bone and cartilage destruction via secretion of matrix metalloproteinases and regulation of monocyte to osteoclast differentiation. In this study we analysed whether DKK1 secretion might contribute to this effect. We hypothesised that synovial fibroblasts from patients with early rheumatoid arthritis would be characterised by high DKK1 expression compared with those from patients with resolving arthritis. MethodsSynovial tissue samples were obtained by ultrasound-guided biopsy from patients with early synovitis within 12 weeks of symptom onset. 12 patients developed rheumatoid arthritis (according to 1987 American College of Rheumatology criteria) and eight had self-limiting disease within 18 months’ follow-up. Synovial fibroblasts were cultured and expanded to passage three with established methods. mRNA expression was quantified with real-time quantitative PCR. DKK1 levels were measured in the supernatants of cultured cells with a commercial ELISA kit (R&D systems). The methylation status of the DKK1 gene promoter was assessed with methylated DNA immunoprecipitation assays. FindingsExpression of DKK1 mRNA was significantly higher in synovial fibroblasts from patients with early rheumatoid arthritis than in those with resolving arthritis (2−dCt relative to glyceraldehyde 3-phosphate dehydrogenase 0·024 vs 0·009, p<0·005). Differential expression was confirmed at the protein level (median 23·2 ng/mL [IQR 11·1–48·5] vs 6·6 ng/mL [4·2–23·6]; p=0·07). Expression levels of DKK1 mRNA or protein did not correlate with disease duration, or with clinical indices. Analysis of DKK1 promoter methylation showed a trend towards promoter hypomethylation in samples from early rheumatoid arthritis compared with resolving samples (1·04-fold enrichment vs 1·52-fold enrichment, not significant). Further samples are being analysed to increase the power of the study. InterpretationDKK1 is an inhibitor of the Wnt signalling pathway that promotes cell invasion and a pro-destruction imbalance of osteoblast and osteoclast activity. Our data suggest that expression of DKK1 by fibroblasts cultured from treatment-naive patients discriminates between persistent and resolving disease, and occurs early in the disease process in rheumatoid arthritis. This difference in gene expression might be under epigenetic control at the level of DNA methylation. Current studies are focusing on validating these findings. FundingWellcome Trust.