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Abstract
Objectives: Midkine (MK) is involved in cell proliferation, differentiation, migration, and survival. In this study, we measured serum MK levels in rheumatoid arthritis (RA) and investigated the correlation of serum MK with RA disease activity. Expression and effect of MK in RA synovial tissue were also examined.
Methods: Serum MK and production of inflammatory mediators by rheumatoid synovial fibroblasts (RSFs) were measured by enzyme-linked immunosorbent assay. MK expression in synovial tissue was examined by immunohistochemistry. MK receptor expression was analyzed by RT-PCR and Western blotting.
Results: RA patients had a significantly higher serum MK level than healthy controls. In RA patients, the MK level was correlated with DAS28-ESR, disability index of the Health Assessment Questionnaire, and rheumatoid factor level. The serum MK level tended to be decreased by anti-TNF therapy. MK was expressed by synovial lining cells in RA synovial tissues and it enhanced the production of IL-6, IL-8, and CCL2 by RSFs. RSFs expressed LDL receptor-related protein 1, candidate receptor for MK.
Conclusions: The serum MK level could be a marker of disease activity in RA and an indicator of a poor prognosis. MK may have a role in the pathogenesis of RA via induction of inflammatory mediators.
Acknowledgements
The authors wish to thank Ms. Sonoko Sakurai for secretarial assistance.
Conflict of interest
Hideaki Shimada received research grant from Cellmid Ltd. Other authors declare that they have no conflicting interests. This work was supported in part by a Project Research Grant (26-25, 27-12) from Toho University School of Medicine to ES; Heisei 23 & 26 Strategic Research Foundation Grants from the Japanese Ministry of Education, Culture, Sports, Science & Technology to Y. A. and S. K.; and a Grant from Japan Society for the Promotion of Science (23591449) to S. K.