Role of hypoxia-regulated HIF transcription factors in RA. In the context of RA pathogenesis, hypoxia-induced stabilization of HIF-α protein can potentially modulate genes that are involved in angiogenesis (for example, VEGF), matrix degradation, apoptosis (for instance, BNIP-3), cellular metabolism (GLUT-1) and inflammation (cytokines and chemokines), thus perpetuating the destructive cascade of reactions. Furthermore, cytokines relevant to RA (IL-1 and TNF) can themselves modulate HIF levels. A schematic representation of a normal and RA joint is shown. Representative sections (×100 magnification, with bars indicating 20 μm) of RA tissue stained for HIF-1α and HIF-2α are shown, taken from two different RA patients. HIF-1α expression appears to be predominantly vascular associated, in areas of diffuse cellular infiltration, unlike HIF-2α, which was frequently associated with infiltrating cells distant form visible blood vessels. BNIP, BCL2/adenovirus E1B 19 kDa-interacting protein; COX, cyclo-oxygenase; GLUT, glucose transporter; HIF, hypoxia-inducible factor; IL, interleukin; MMP, matrix metalloprotease; RA, rheumatoid arthritis; TNF, tumour necrosis factor; VEGF, vascular endothelial growth factor.