Midkine, a heparin-binding growth factor, is fundamentally involved in the pathogenesis of rheumatoid arthritis
Article first published online: 6 MAY 2004
Copyright © 2004 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 50, Issue 5, pages 1420–1429, May 2004
How to Cite
Maruyama, K., Muramatsu, H., Ishiguro, N. and Muramatsu, T. (2004), Midkine, a heparin-binding growth factor, is fundamentally involved in the pathogenesis of rheumatoid arthritis. Arthritis & Rheumatism, 50: 1420–1429. doi: 10.1002/art.20175
- Issue published online: 6 MAY 2004
- Article first published online: 6 MAY 2004
- Manuscript Accepted: 16 JAN 2004
- Manuscript Received: 13 OCT 2003
- Ministry of Education, Culture, Sports, Science, and Technology. Grant Numbers: 15590270, 15390103, 14082202
- Japan Rheumatism Foundation
Midkine (MK), a heparin-binding growth factor, promotes growth, survival, and migration of various cells. The essential role of MK in migration of inflammatory cells has been shown using mice deficient in the MK gene (Mdk−/− mice). We undertook this study to investigate the role of MK in the pathogenesis of rheumatoid arthritis (RA).
MK levels in specimens from patients were determined by enzyme-linked immunosorbent assay, and localization of MK was revealed by immunohistochemical analysis. Susceptibility to antibody-induced arthritis was compared between Mdk−/− and wild-type (WT) mice. Osteoclast differentiation was monitored using macrophage-like cells isolated from human synovial tissue and macrophages from mouse bone marrow.
MK levels in sera and synovial fluid were increased in most RA patients, indicating a strong correlation between MK expression and RA. MK was expressed in macrophage-like cells and fibroblast-like cells in synovial membranes from the patients. In antibody-induced arthritis, Mdk−/− mice seldom developed the disease, while most of the WT mice did. Administration of MK to the Mdk−/− mice increased the frequency of antibody-induced arthritis. Migration of inflammatory leukocytes to the synovial membranes in the disease model was suppressed in the Mdk−/− mice. Furthermore, MK was found to promote the differentiation of osteoclasts from macrophages.
MK participates in each of the two distinct phases of RA development, namely, migration of inflammatory leukocytes and osteoclast differentiation, and is a key molecule in the pathogenesis of RA.