Background Mechanisms preventing the resolution of inflammation and promoting joint damage underlie the persistence of RA and the development of damage early in disease. Dickkopf related protein 1 (DKK1) is an inhibitor of the Wnt signalling pathway involved in osteoblast growth and differentiation and cell adhesion and invasion in health and disease. In cancer, increased plasma levels of DKK1 are associated with osteolytic lesions in multiple myeloma and with solid tumour invasion and progression. In rheumatoid arthritis (RA), increased DKK1 plasma levels correlate with inflammation and the presence of bone erosions
Objectives We aimed to identify differences in expression of key stromal genes including DKK1 in synovial fibroblasts from patients from three different clinical outcome groups: very early RA, established RA and spontaneously resolving arthritis
Methods Synovial tissue biopsies were obtained from 12 early synovitis patients who developed RA (according to 1987 ACR criteria within 18 month follow-up) and 8 early synovitis patients with self-limiting disease. All samples were collected within 12 weeks of the onset of any musculoskeletal symptom attributed to inflammatory arthritis. In addition, 9 patients with established RA (according to 1987 ACR criteria with a symptom duration of >3 months at sample collection), were studied. Synovial fibroblasts were cultured and expanded to passage 3 using established methods. mRNA expression for a range of stromal genes was quantified using real-time quantitative PCR. Values were expressed as 2-dCt relative to GAPDH. DKK1 levels were measured in the supernatants of cultured cells using a commercial ELISA kit (R&D sytems)
Results Amongst differentially expressed genes, DKK1 expression was significantly higher in synovial fibroblasts from patients with early RA than in those from patients with resolving arthritis (0.024 vs. 0.009, p<0.005). Differential expression was also observed at the protein level (23.2 ng/ml (11.1-48.5) vs. 6.6 ng/ml (4.2-23.6), p=0.07). There was no differential expression of DKK1 in early RA and established RA groups. Expression levels of DKK1 mRNA or protein did not correlate with disease duration, or with clinical indices
Conclusions DKK1 is an inhibitor of the Wnt signalling pathway that has been shown to promote 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 RA
Disclosure of Interest None Declared
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