Blocking Tie-2 as a treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is one of the more common autoimmune diseases along with multiple sclerosis (MS), type I diabetes and Crohn’s disease. Approximately one in five people in the western world suffer from autoimmune diseases and some estimates indicate that 75% of these are women. An estimated 5 million individuals suffer from RA, a figure which will increase to 5.7 million by 2010.

Different autoimmune conditions are often treated with the same medicines and broad-spectrum anti-inflammatory drugs are widely used. Since the launch of the modern pharmaceutical industry just over 100 years ago with the synthesis of aspirin, the large class of non-steroidal aspirin-like anti-inflammatory drugs (NSAIDs) has been the mainstay of the treatment of rheumatoid and other forms of arthritis. It is generally accepted that NSAIDs relieve the symptoms of arthritis such as pain and swelling without changing the course of underlying disease. According to some analysts, new therapeutic approaches will cause the market for autoimmune disorder treatments to grow at an annual rate of over 15% to a value of over $21 billion by 2006. This market expansion along with the need for improved treatments of rheumatoid arthritis has driven the development drugs which modify disease progression (click here for our new overview of this field).

One field of disease modifying drugs has focused on angiogenesis. The joint in RA contains massive proliferating synovium, which forms an invading tissue termed pannus and persistent angiogenesis is critical to maintaining the chronic architectural changes in the RA synovium via delivery of nutrients and inflammatory cells. Although the importance of angiogenesis in arthritis progression has been well recognized, the molecular mechanisms promoting angiogenesis in RA have not been clearly identified. In their recent paper DeBusk et al report the central role of Tie2 in this process.

Tie2 is an endothelium-specific receptor tyrosine kinase that is activated by angiopoietin 1 and which has previously been shown to be critical for vascular development. The Tie2/angiopoietin 1 axis has been shown to be up-regulated in psoriasis and in breast cancer tissue and blocking Tie2 action inhibits tumor angiogenesis and tumor growth. Tie2 protein and angiopoietin 1 mRNA have also been detected in RA synovium. TNF-alpha plays a major role in regulating inflammation and angiogenesis in RA synovium. Synovial fluids from RA patients induce angiogenesis partly through the TNF-alpha pathway, blocking of which inhibits vascularity in synovium and since TNF-alpha regulates Tie2 expression in endothelial cells it is possible that Tie2 mediates this effect. In the September edition of Arthritis & Rheumatism, DeBusk et al report that Tie2 and angiopoietin 1 are expressed in endothelial cells and synoviocyte/inflammatory cell respectively in human RA synovium and that Tie2 mediates angiogenesis in joint tissue taken from animals with collagen-induced arthritis (CIA). At a molecular level the ability of TNF-alpha to increase angiogenesis resulted from an NF-kappaB-mediated increase in Tie2 expression as well as an increase in angiopoietin 1 activity.

This study makes a convincing case for the development of Tie2 inhibitors as a treatment of RA. Regular readers of TherapeuticAdvances may be aware of the “Kinase Enterprise library” recently featured by LeadDiscovery. This is a targeted library of candidate kinase inhibitors that is available for in house screening and screening of this library for other inhibitors of Tie2 may be of immense benefit to companies involved in RA therapeutics (Click here for further information on this library).