Inhibition of HDAC Activity by ITF2357 Ameliorates Joint Inflammation and Prevents Cartilage and Bone Destruction in Experimental Arthritis

Leo A B Joosten,Paolo Mascagni,Flavio Leoni,Sajeda Meghji

doi:10.2119/molmed.2011.00058

Abstract

Inhibition of histone deacetylases (HDAC) has been shown to modulate gene expression and cytokine production after stimulation with several stimuli. In the present study, the antiinflammatory effect of a potent HDACi, ITF2357, was explored in different experimental models of arthritis. In addition, the bone protective effect of ITF2357 was investigated in vitro. Treatment of acute arthritis (Streptococcus pyogenes cell wall [SCW] arthritis) with ITF2357 showed that joint swelling and cell influx into the joint cavity were reduced. Furthermore, the chondrocyte metabolic function was improved by treatment of ITF2357. The production of proinflammatory cytokines by synovial tissue was reduced after ITF2357 treatment. To examine the effect of HDAC inhibition on joint destruction, ITF2357 was applied to both rat adjuvant arthritis and mouse collagen type II arthritis. ITF2357 treatment both ameliorates the severity scores in arthritis models and prevents bone destruction. In an in vitro bone destruction assay, ITF2357 was highly effective at a dose of 100 nmol/L. In conclusion, inhibition of HDAC prevents joint inflammation and cartilage and bone destruction in experimental arthritis.

Highlights

Synthetic histone deacetylases inhibitors (HDACi) hyperacetylate histones via the conserved N-terminal lysines present on histones, they hyperacetylate cytoplasmic proteins, including transcription factors
In order to be used during chronic disease states, such as occurs with inflamed joints, HDACi need to be safe for long-term use
We have evaluated the effect of ITF2357 in several models of arthritis, ranging from acute to chronic models of arthritis

Summary

INTRODUCTION

Synthetic histone deacetylases inhibitors (HDACi) hyperacetylate histones via the conserved N-terminal lysines present on histones, they hyperacetylate cytoplasmic proteins, including transcription factors. Micromolar concentrations of synthetic HDAC inhibitors are required to increase the expression of several proapoptotic genes in malignant cells [4,6,7,8]. HDAC INHIBITORS DECREASE CYTOKINE PRODUCTION BY RA SYNOVIAL CELLS AND RA TISSUE EXPLANTS. It was shown that HDAC inhibitors suppress cytokine production by RA synovial tissue explants and that both TNFα- and LPS-induced cytokine and chemokine production were decreased by inhibition of HDAC activity [19]. HDACi suppress cytokine production without an effect on cell death, which is of high interest This indicates that it might be possible to uncouple inhibition of cytokine production and induction of apoptosis [14]

INHIBITION OF HDAC ACTIVITY SUPPRESSES EXPERIMENTAL ARTHRITIS

REVIEW ARTICLE

Findings

Necrotic and Periarticular