Anti‐rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen‐induced arthritis in rodents

Abstract

Background and purpose: Rheumatoid arthritis (RA) is a chronic inflammatory disease. Histone deacetylase inhibitors (HDACi), a new class of anti‐cancer agents, have recently been reported to exhibit potent anti‐inflammatory activities. A proof of concept study was carried out with suberoylanilide hydroxamic acid (SAHA) and MS‐275, two HDACi currently undergoing clinical investigations for various oncological indications. Experimental approach: The anti‐rheumatic effects of SAHA and MS‐275 were assessed in both mouse and rat collagen induced arthritis (CIA) models. Key results: SAHA exhibited moderate prophylactic efficacy. It attenuated paw swelling due to inflammation, decreased bone erosion in both mice and rats and reduced slightly the RA‐induced bone resorption in rats. However, SAHA could not inhibit the onset of arthritis. In contrast, MS‐275 displayed dramatic anti‐rheumatic activities. In prophylactic intervention, high doses of MS‐275 prevented bone erosion and markedly delayed the onset of arthritis; at low doses, MS‐275 strongly attenuated paw swelling, bone erosion, and bone resorption associated with RA. Furthermore, the therapeutic efficacy of MS‐275 was also documented. After the onset of arthritis, it could stop the disease progression and joint destruction. An anti inflammatory effect of MS‐275 was also confirmed through its capacity to decrease serum IL‐6 and IL‐1β levels in the CIA induced mouse model. The anti‐rheumatic activity of MS‐275 was also confirmed through histological observation. No synovial hyperplasia, pannus formation, cartilage or bone destruction were observed in the high dose prophylactic intervention in mice. Conclusion and implication: This study strongly supported HDACi as an innovative therapeutic strategy for RA. British Journal of Pharmacology (2007) 150, 862–872. doi:10.1038/sj.bjp.0707165