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Novel Therapeutic Approach to Treatment of Arthritic Disease is Explored by Scientists at The Scripps Research Institute

La Jolla, CA. January 1, 1999 – Scientists at The Scripps Research Institute (TSRI) have studied an investigational anti-angiogenesis treatment previously employed against various forms of cancer to assess its impact on arthritic disease in an animal model. Their results, published today in The Journal of Clinical Investigation, provide evidence for a central pathogenic contribution of angiogenic blood vessels to the maintenance and severity of arthritic disease, and the potential viability of anti-angiogenic therapy for the treatment of rheumatoid arthritis.

The article, "Decreased Angiogenesis and Arthritic Disease in Rabbits Treated with an alpha v beta 3 Antagonist," is authored by Chris M. Storgard, M.D., Dwayne G. Stupack, Ph.D., and David A. Cheresh, Ph.D., together with their collaborators Alfred Jonczk, Ph.D.,Simon L. Goodman, Ph.D., and Robert I. Fox, M.D., Ph.D.

According to David Cheresh, Ph.D., Professor, Department of Immunology, TSRI , "While angiogenesis has been associated with rheumatoid arthritis, our study implicates angiogenesis as a major factor in its progression. Moreover, it appears that the same anti-angiogenesis strategy that impacts tumor growth may also impact the progression of rheumatoid arthritis."

While rheumatoid arthritis has been classified as an angiogenesis-associated disease, scientists have not yet determined whether angiogenesis the growth of new blood vessels directly participates in arthritic disease or is a consequence of ongoing inflammation. This paper provides evidence that angiogenesis contributes to arthritic disease.

A joint affected by rheumatoid arthritis is characterized by the proliferation of the synovial lining forming excessive folds of inflamed tissue, termed pannus. Pannus formation is thought to be central to the process of joint destruction. Angiogenesis appears to be required for pannus development, and plays a role in inflammation as a source of cytokine and protease activity. Although the specific factors that promote angiogenesis in rheumatoid arthritis have not been identified, synovial tissue and fluid contain angiogenesis-promoting molecules.

According to Cheresh, "Not only did bFGF, an angiogenic producer, accelerate arthritis in this model, but importantly an antagonist of integrin alpha v beta 3, which targets angiogenic blood vessels, inhibited angiogenesis and reduced the severity of arthritis. Joint swelling synovial infiltrate, pannus formation and the incidence of cartilage erosions were all significantly reduced in animals treated early with this integrin antagonist. Inhibition of neovascularization in this model may influence many parameters of disease, including inflammation, protease production and tissue metabolism."

Previous studies conducted in the Cheresh lab for the past several years suggested targeting alpha v beta 3 on blood vessel cells within malignant tumors as a way to cut off the source of nourishment to the tumors. Focusing on one of the integrin receptor molecules -- alpha v beta 3 - - preferentially expressed on newly sprouting vessels, the researchers demonstrated the ability of an antibody, LM609, to block the integrin and thereby block new blood vessel growth. Further, the advantage of this approach lies in its ability to disrupt a process common to angiogenesis no matter how it is initiated. In fact, these studies have now progressed to clinical trials, in which patients with late stage cancer have begun to be treated.

In the current study, treatment directed against integrin alpha v beta 3 was evaluated for its impact on arthritic disease in an animal model of rheumatoid arthritis. The administration of the integrin antagonist resulted in an increase in vascular apoptosis -- programmed cell death -- leading to the inhibition of synovial angiogenesis, as well as a reduction in joint swelling and pannus formation in both early and established arthritis. Further, the treatment provided protection against the development of cartilage erosion.

Cheresh commented, "The fact that this antagonist was effective when administered in the chronic arthritis model is relevant to future clinical applications. The expression of the integrin on synovial blood vessels in human rheumatoid arthritis presents an opportunity to pursue alpha v beta 3 integrin-directed anti-angiogenic therapy for the treatment of rheumatoid arthritis."

This work was supported by grants from the National Institutes of Health, the Department of Academic Affairs of Scripps Clinic, the Arthritis Foundation, the Canadian Arthritis Society, the Joseph Drown Foundation, and Merck KGAa, Darmstadt, Germany.

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