Angiogenesis and arthritis: a potential therapeutic target?

Musculoskeletal disorders such as rheumatoid arthritis (RA) are a common cause of pain and disability. Over the past decade, advances in understanding RA pathogenesis, based on studies of human cells and animal models of disease, have led to the identification of new targets for therapeutic intervention. Nevertheless, despite the clinical success of anticytokine biologicals, further initiatives in understanding RA pathogenesis to aid further drug discovery are highly desirable.

An early event in RA is an alteration in synovial blood vessel density. The hyperplasia of the synovium necessitates a compensatory increase in the number of blood vessels to nourish and oxygenate the tissue. A key response to increased requirement for nutrients and/or reduced oxygen is to form new blood vessels (angiogenesis). In RA, the synovial blood vessel number has been found to correlate with hyperplasia, mononuclear cell infiltration and indices of joint tenderness. Endothelial cells lining blood vessels within RA synovium have been shown to express cell-cycle antigens. A variety of angiogenic mediators, including cytokines and growth factors, have been identified in rheumatoid joints. We and other workers have shown that expression of the angiogenic factor vascular endothelial growth factor (VEGF) is increased in RA. Importantly, circulating levels of VEGF are elevated in patients with established RA and are reduced by anti-tumour necrosis factor alpha antibody treatment, suggesting that part of the beneficial effect of anti-tumour necrosis factor alpha in RA may be reduced angiogenesis.

However, new blood vessel formation may not keep pace with synovial proliferation leading to regions of hypoperfusion. Intra-articular oxygen tension is significantly lower in RA patients when compared with controls, and hypoxia-inducible transcription factors such as HIF-1α and HIF-2α are significantly upregulated. Of relevance in the context of RA, VEGF is significantly upregulated by hypoxia, which would promote further blood vessel formation. As well as being a key angiogenic factor, VEGF also promotes vascular endothelial cell survival, by increasing expression of anti-apoptotic proteins such as Bcl-2, and members of the inhibitor of apoptosis family (namely cIAP-1, XIAP and survivin), which directly bind to and inhibit caspases. Our data suggest that induction of these apoptosis inhibitors is mediated via the NF-κB pathway.

We are currently further investigating pathways activated by VEGF, as well as dissecting out the response of synovial cells to hypoxia, both in terms of induction of angiogenic molecules such as VEGF and upregulation of inflammatory cytokines such as tumour necrosis factor alpha. There have been a number of studies showing that angiogenesis blockade is effective in animal models of arthritis. Since VEGF is elevated early during the course of RA, and since RA is most active in the initial stages of disease, early treatment might reduce subsequent joint erosion and damage. RA may be a potential target for anti-angiogenic therapy, and targeting VEGF may prove to be especially beneficial.