Hypoxia. The role of hypoxia and HIF-dependent signalling events in rheumatoid arthritis.

An adequate supply of oxygen and nutrients is essential for survival and metabolism of cells, and consequentially for normal homeostasis. Alterations in tissue oxygen tension have been postulated to contribute to a number of pathologies, including rheumatoid arthritis (RA), in which the characteristic synovial expansion is thought to outstrip the oxygen supply, leading to areas of synovial hypoxia and hypoperfusion. Indeed, the idea of a therapeutic modality aimed at 'starving' tissue of blood vessels was born from the concept that blood vessel formation (angiogenesis) is central to efficient delivery of oxygen to cells and tissues, and has underpinned the development of anti-angiogenic therapies for a range of cancers. An important and well characterized 'master regulator' of the adaptive response to alterations in oxygen tension is hypoxia-inducible factor (HIF), which is exquisitely sensitive to changes in oxygen tension. Activation of the HIF transcription factor signalling cascade leads to extensive changes in gene expression, which allow cells, tissues and organisms to adapt to reduced oxygenation. One of the best characterized hypoxia-responsive genes is the angiogenic stimulus vascular endothelial growth factor, expression of which is dramatically upregulated by hypoxia in many cells types, including RA synovial membrane cells. This leads to an apparent paradox, with the abundant synovial vasculature (which might be expected to restore oxygen levels to normal) occurring nonetheless together with regions of synovial hypoxia. It has been shown in a number of studies that vascular endothelial growth factor blockade is effective in animal models of arthritis; these findings suggest that hypoxia may activate the angiogenic cascade, thereby contributing to RA development. Recent data also suggest that, as well as activating angiogenesis, hypoxia may regulate many other features that are important in RA, such as cell trafficking and matrix degradation. An understanding of the biology of the HIF transcription family may eventually lead to the development of therapies that are aimed at interfering with this key signalling pathway, and hence to modulation of hypoxia-dependent pathologies such as RA.