Rheumatoid Arthritis (RA) is a chronic inflammatory disease of the synovial joints that affects about 1% of the U.S. population. One of the major cell types of the synovium, the fibroblast-like synoviocytes (FLS), play a prominent role in theMoreRheumatoid Arthritis (RA) is a chronic inflammatory disease of the synovial joints that affects about 1% of the U.S.
population. One of the major cell types of the synovium, the fibroblast-like synoviocytes (FLS), play a prominent role in the pathology of RA. In the diseased state, the FLS become actively involved in the joint damage and the chronic inflammation. It is unclear what brings about the aggressive phenotypes of the FLS. One possibility is stimulation by tumor necrosis factor alpha (TNFalpha), a potent pro-inflammatory cytokine that has a well-established role in the propagation of the disease. To determine if TNFalpha plays a role in the change of FLS behavior, a microarray analysis of all TNFalpha-inducible genes of normal rat FLS was carried out.
141 genes were at least two-fold up-regulated, while 64 genes were two-fold or more down-regulated. Comparison of the TNFalpha-induced expression profile of the normal rat FLS to published data on those of human RA FLS revealed that TNFalpha elicits similar gene expressions changes in FLS regardless of the disease state, strongly suggesting that TNFalpha-induced signaling is an intrinsic and not disease-dependent phenomenon.-Anti-TNFalpha therapies have been one of the most successful RA treatments, but there are shortcomings of these drugs that should be improved upon.
p38 mitogen-activated protein kinase (MAPK) is a major downstream effector of TNFalpha signaling whose inhibition could be a potential alternative therapeutic strategy. A genome-wide analysis of all genes regulated by the p38 MAPK in the TNFalpha signaling pathway in the FLS revealed that one third of the genes inducible by TNFalpha were affected by a classic p38 MAPK inhibitor, SB203580, many of them already have established connections to rheumatoid arthritis.-The relevance of the TNFalpha induction and p38 MAPK inhibition is exemplified by the study on the expression changes and function of Cxcl2, a neutrophil chemotactic chemokine that is most highly up-regulated by TNFalpha from the microarray profile and whose activation is p38 MAPK dependent.-This dissertation shows that the TNFalpha signaling pathway is intrinsic to the FLS, regardless of its activation state.
It also extends our knowledge of biological processes regulated by p38 MAPK and reaffirms the concept that blockade of the p38 MAPK pathway could be a good drug target for treatment of RA.