A therapeutic strategy uses histone deacetylase inhibitors to modulate the expression of genes involved in the pathogenesis of rheumatoid arthritis

Mol Ther. 2003 Nov;8(5):707-17. doi: 10.1016/s1525-0016(03)00235-1.


Rheumatoid arthritis (RA) is characterized by progressive destruction of the affected joints. The pathophysiology results from genetic susceptibility and autoimmune phenomena, leading to tissue inflammation and synovial hyperplasia termed pannus, which irreversibly destroys cartilage and bone. The current treatment options, which suppress immune responses or ameliorate inflammation, do not halt the destructive process. We found that the histone deacetylase (HDAC) inhibitors (phenylbutyrate and trichostatin A) causing histone hyperacetylation to modulate multiple gene expression not only induced the expression of p21(Cip1) and p16(INK4) in synovial cells but also inhibited the expression of tumor necrosis factor-alpha in affected tissues in adjuvant arthritis, an animal model of RA. Based on the observations that joint swelling is reduced, subintimal mononuclear cell infiltration is decreased, synovial hyperplasia is inhibited, pannus formation is suppressed, and no cartilage or bone destruction is seen, the HDAC inhibitors may represent a new class of compounds for the treatment of RA by simultaneously, coordinately, synergistically, or epigenetically modulating multiple molecular targets in the pathogenesis of RA.

MeSH terms

  • Acetylation
  • Animals
  • Arthritis, Rheumatoid / drug therapy*
  • Blotting, Western
  • Cell Division
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / metabolism
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Regulation / drug effects
  • Histone Deacetylase Inhibitors*
  • Histones / metabolism
  • Hydroxamic Acids / therapeutic use
  • Immunohistochemistry
  • Inflammation / drug therapy
  • Leukocytes, Mononuclear / metabolism
  • Male
  • Phenylbutyrates / therapeutic use
  • Rats
  • Rats, Long-Evans
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism


  • Cdkn1a protein, rat
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • Phenylbutyrates
  • Tumor Necrosis Factor-alpha
  • trichostatin A