Midkine, a heparin-binding growth factor, is fundamentally involved in the pathogenesis of RA

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Arthritis Rheum. 2004 May;50(5):1420-9.

Midkine, a heparin-binding growth factor, is fundamentally involved in

the pathogenesis of rheumatoid arthritis.

Maruyama K, Muramatsu H, Ishiguro N, Muramatsu T.

Department of Biochemistry, Nagoya University Graduate School of

Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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.

CONCLUSION: 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.

PMID: 15146411

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