Class I Histone Deacetylase Inhibition Modulates Metalloproteinase Expression and Blocks Cytokine-Induced Cartilage Degradation

Arthritis Rheum. 2013 Jul;65(7):1822-30. doi: 10.1002/art.37965.

Abstract

Objective: To examine the ability of a broad-spectrum histone deacetylase (HDAC) inhibitor to protect cartilage in vivo, and to explore the effects of class-selective HDAC inhibitors and small interfering RNA (siRNA)-induced knockdown of HDACs on metalloproteinase expression and cartilage degradation in vitro.

Methods: A destabilization of the medial meniscus (DMM) model was used to assess the in vivo activity of the HDAC inhibitor trichostatin A (TSA). Human articular chondrocytes (HACs) and SW-1353 chondrosarcoma cells were treated with cytokines and TSA, valproic acid, MS-275, or siRNA, and quantitative reverse transcription-polymerase chain reaction was performed to determine the effect of treatment on metalloproteinase expression. HDAC inhibitor activity was detected by Western blotting. A bovine nasal cartilage (BNC) explant assay was performed to measure cartilage resorption in vitro.

Results: Systemically administered TSA protected cartilage in the DMM model. TSA, valproic acid, and MS-275 repressed cytokine-induced MMP1 and MMP13 expression in HACs. Knockdown of each class I HDAC diminished interleukin-1-induced MMP13 expression. All of the HDAC inhibitors prevented degradation of BNC, in which TSA and MS-275 repressed cytokine-induced MMP expression.

Conclusion: Inhibition of class I HDACs (HDAC-1, HDAC-2, HDAC-3) by MS-275 or by specific depletion of HDACs is capable of repressing cytokine-induced metalloproteinase expression in cartilage cells and BNC explants, resulting in inhibition of cartilage resorption. These observations indicate that specific inhibition of class I HDACs is a possible therapeutic strategy in the arthritides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / pharmacology*
  • Cattle
  • Cell Line, Tumor
  • Cells, Cultured
  • Chondrocytes / drug effects*
  • Chondrocytes / metabolism
  • Disease Models, Animal
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histones / drug effects
  • Histones / metabolism
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Metalloproteases / drug effects*
  • Metalloproteases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nasal Cartilages / drug effects*
  • Nasal Cartilages / metabolism
  • Osteoarthritis, Knee*
  • Pyridines / pharmacology*
  • RNA, Small Interfering / pharmacology
  • Tubulin / drug effects
  • Tubulin / metabolism

Substances

  • Benzamides
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • Pyridines
  • RNA, Small Interfering
  • Tubulin
  • entinostat
  • trichostatin A
  • Metalloproteases