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

Br J Pharmacol. 2007 Apr;150(7):862-72. doi: 10.1038/sj.bjp.0707165. Epub 2007 Feb 26.


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-1beta 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Experimental / blood
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Experimental / pathology
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / pathology
  • Benzamides / therapeutic use*
  • Female
  • Histone Deacetylase Inhibitors*
  • Hydroxamic Acids / therapeutic use*
  • Interleukin-1beta / blood
  • Interleukin-6 / blood
  • Male
  • Metatarsal Bones / drug effects
  • Metatarsal Bones / pathology
  • Mice
  • Mice, Inbred DBA
  • Pyridines / therapeutic use*
  • Rats
  • Rats, Inbred Strains
  • Vorinostat


  • Antirheumatic Agents
  • Benzamides
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Interleukin-1beta
  • Interleukin-6
  • Pyridines
  • entinostat
  • Vorinostat