Differentially Expressed Epigenome Modifiers, Including Aurora Kinases A and B, in Immune Cells in Rheumatoid Arthritis in Humans and Mouse Models

Abstract

Objective The aim of this study was to identify epigenetic factors that are implicated in the pathogenesis of rheumatoid arthritis (RA) and to explore the therapeutic potential of the targeted inhibition of these factors. Methods PCR arrays were utilized to investigate the expression profile of genes that encod key epigenetic regulator enzymes. Mononuclear cells from RA patients and mice were monitored for gene expression changes, in association with arthritis development in murine models of RA. Selected genes were further characterized by quantitative real-time PCR, Western blot and flow cytometry methods. The targeted inhibition of the upregulated enzymes was studied in arthritic mice. Results A set of genes with arthritis-specific expression was identified by the PCR arrays. Aurora kinase A and B, both of which were highly expressed in arthritic mice and treatment naïve RA patients, were selected for detailed analysis. Elevated Aurora kinase expression was accompanied with an increased phosphorylation of histone H3, which promotes proliferation of T lymphocytes. Treatment with VX-680, a pan-Aurora kinase inhibitor, promoted B cell apoptosis, provided significant protection against the onset, and attenuated the inflammatory reactions in arthritic mice. Conclusions Arthritis development is accompanied the changes in the expression of a number of epigenome-modifying enzymes. Drug-induced downregulation of the Aurora kinases, among other targets, seems to be sufficient to treat experimental arthritis. Development of new therapeutics that target the Aurora kinases can potentially improve RA management.

Histone variants expression in peripheral blood mononuclear cells of patients with rheumatoid arthritis

“…13,14 Taken together, these studies suggest that epigenetic aberrations can cause and certainly mediate autoimmune disease progression. 15 Recently, a study on epigenetic alterations in PBMCs of RA patients was conducted by Glant et al 16 They showed that epigenome modifiers are differentially expressed in RA versus control patients. Unfortunately, in the study by Glant et al, the expression of histone variants was not examined.…”

Epigenetics in the pathogenesis of rheumatoid arthritis

“…Our group performed the first study on arthritis-related epigenetic modifiers [20], in which chromatin-modifying enzymes were analyzed in B and T cells from arthritic mice and peripheral blood mononuclear cells from patients with RA. All chromatin-modifying enzyme families were represented in the repertoire of genes with arthritis-specific expression, including histone kinases, acetyltransferases, deacetylases, methyltransferases and demethylases, as well as ubiquitin ligases.…”

Immune consequences of kinase inhibitors in development, undergoing clinical trials and in current use in melanoma treatment

“…Another study demonstrated elevated aurora kinase A and B expression in arthritis, which was correlated to promotion of T-cell proliferation via increased histone H3 phosphorylation. This latter study also found increased B-cell apoptosis following treatment with a pan-aurora kinase inhibitor (VX680) [195].…”