Epitope plays a key role in the development of rheumatoid arthritis

Rheumatoid arthritis is a chronic inflammatory disease characterized by joint destruction. It has been suggested that the extracellular matrix protein osteopontin (OPN), which is expressed by a number of different mediators of the immune response, may facilitate this destruction. In the July 15 issue of The Journal of Clinical Investigation, Nobuchika Yamamoto and colleagues from the Fujisawa Pharmaceutical Company in Japan, provide important new evidence indicating a role for OPN in the pathogenesis of inflammatory arthritis and associated joint destruction.

OPN is abundant in bone, where it facilitates cell adhesion and modulation of the immune response. This adhesion is facilitated by interaction with a variety of cell surface molecules known as integrins. Binding of OPN to these cell surface molecules generally occurs at a specific integrin-binding motif. A second sequence, (SLAYGLR in mice and SVVYGLR in humans) within OPN has also been shown to mediate this cell adhesion. The site is the result of cleavage of human OPN by the protease thrombin and promotes the adherence of cells expressing intergrins a4 and a9.

In their latest report, Yamamoto and colleagues observed that monocytes of arthritic mice had a greater tendency to migrate toward thrombin-cleaved OPN, than full-length OPN, and that these monocytes expressed integrins a4 and a9 that bind the SLAYGLR epitope. Furthermore, the authors demonstrated that antibody blockade of the SLAYGLR sequence stopped monocyte migration to the cleaved OPN and significantly suppressed the development of arthritis in mice. The study indicates the critical role of the SLAYGLR sequence in the pathogenesis of rheumatoid arthritis in mice.

"The effects on the clinical and histologic parameters studied provide convincing additional evidence for a role of OPN in arthritic inflammation, and specifically in the recruitment of inflammatory cells to arthritic joints" stated Dr. Ellen Gravallese from Beth Israel Deaconess Medical Center and Harvard Institutes of Medicine in her accompanying commentary. She continues "given the clear and important role of OPN in inflammatory processes and bone remodeling, it will be of considerable interest to resolve some of the remaining controversies regarding the role of OPN in this disease".

TITLE: Essential role of the cryptic epitope SLAYGLR within osteopontin in a murine model of rheumatoid arthritis

AUTHOR CONTACT:
Nobuchika Yamamoto
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan.
Phone: 81-029-847-8611
Fax: 81-029-847-1536
Email: nobuchika_yamamoto@po.fujisawa.co.jp

View the PDF of this article at: http://www.jci.org/cgi/content/full/112/2/181

ACCOMPANYING COMMENTARY:
Osteopontin: a bridge between bone and the immune system

AUTHOR CONTACT:
Ellen M. Gravellese
Harvard University, Boston, Massachusetts, USA.
Phone: 617-667-0717
Fax: 617-975-5299
Email: egravall@bidmc.harvard.edu

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