Not surprisingly, the most nota ble alterations occurred in the expression of genes involved in inflammation and tissue remodelling. TNFa and IL 1b, as well as playing roles in the inflammatory component selleck chem inhibitor of RA, modulate synovial angiogenesis by inducing the pro duction of angiogenic mediators like VEGF, ANG 1, ANG 2 and TIE 2 by RA synoviocytes. Inhibitors,Modulators,Libraries MMPs participate in angiogenesis by degrading and remodelling the extracellular matrix and basement membranes, allow ing activated endothelial cells to proliferate and migrate, as well as releasing extracellular matrix bound growth fac tors such as FGF 2, VEGF or IGF 1. Our results further indicate that a hypoxic and pro inflammatory microenvironment induces the transcrip tional activation of angiogenic growth factors in arthritic joints of CIA mice, including midkine and Hgf.

Elevated levels of midkine have been detected in the serum and synovial fluid of RA patients, and HGF levels within the arthritic joint correlate with Inhibitors,Modulators,Libraries disease activity and synovial microvessel density. On the other hand, EGF, which has been reported as elevated in RA synovial fluids, was down regulated during CIA. Further, we detected a significant decrease of leptin mRNA levels in arthritic Inhibitors,Modulators,Libraries paws, which is consistent with published gene expression data in murine CIA. Leptin, apart from the regulation of food intake, has been implicated in the regulation of immune responses and angiogenesis. Although the mRNA levels of VEGF isoforms and Plgf were only modestly altered during CIA, the VEGF signalling pathway was clearly affected, since the expression of its tyrosine kinase receptors Flt 1 and Flk 1 as well as its co Inhibitors,Modulators,Libraries receptors Nrp 1 and Nrp 2 was sig nificantly Inhibitors,Modulators,Libraries increased during CIA.

This relatively small increase in Vegf expression was unexpected, especially in view of data showing high VEGF secretion by mouse CIA synovial membrane cells or the effectiveness selleck of anti VEGF treatment in experimental arthritis. How ever, the difference in VEGF mRNA levels or protein levels between non arthritic and arthritic tissue was also reported to be not more than 1. 5 to 1. 6 fold. Taken together, these findings indicate that in the CIA model, VEGF expression does not change markedly, but seems nonetheless sufficient to induce pathological angiogen esis, and suggest that VEGF mediated angiogenesis is lar gely modulated through an increase in surface expression of VEGF receptors on target cells, thereby increasing their responsiveness towards the angiogenic stimuli. Another pathway involved in vessel formation and maturation is the ANG TIE system.