IKKbeta and p53 as therapeutic targets for arthritis

Abstract

The disparity between the proportion of cells with DNA strand breaks and the low number of apoptotic cells in rheumatoid synovial tissue suggests impaired apoptosis. Therefore, therapeutic strategies aimed at induction of apoptosis in rheumatoid synovial tissue may be attractive. Adjuvant arthritis (AA) in rats is among the most commonly used model for rheumatoid arthritis (RA). To characterize the extent to which apoptosis occurs in the natural course of the disease, we evaluated the number of apoptotic cells and the expression of p53 in various phases of AA. We found that significant apoptosis only occurs late in AA and this is concordant with marked p53 overexpression, making it a useful model for testing proapoptotic therapies. Intra-articular adenoviral gene transfer of wild-type p53 resulted in an incremental increase in p53 expression in the injected joints, but this therapy did not have a beneficial clinical effect, since there was already dramatic p53 overexpression in the later stages of AA. NF-κB activation is another factor involved in the persistent activation of synovial cells and impaired apoptosis. IκB kinase β (IKKβ) is a key regulator of NF-κB. We observed the development of arthritis after intra-articular adenoviral gene transfer of IKKβ-wt into the joints of normal rats. Increased IKK activity was detectable in the Ad.IKKβ-wt injected ankle joints, coincident with enhanced NF-κB binding activity. Conversely, intra-articular gene transfer of Ad.IKKβ-dn significantly ameliorated the severity of adjuvant arthritis in Lewis rats. This effect was accompanied by a significant decrease in levels of NF-κB binding activity. Targeting IKK activity may represent a valid new strategy for the treatment of RA.