title: Class I histone deacetylase inhibition modulates metalloproteinase expression and blocks cytokine-induced cartilage degradation.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of East Anglia, Norwich, UK.
authors.forename: Kirsty L
authors.initials: KL
authors.lastname: Culley
authors.forename: Wang
authors.initials: W
authors.lastname: Hui
authors.forename: Matt J
authors.initials: MJ
authors.lastname: Barter
authors.forename: Rose K
authors.initials: RK
authors.lastname: Davidson
authors.forename: Tracey E
authors.initials: TE
authors.lastname: Swingler
authors.forename: Auriane P M
authors.initials: AP
authors.lastname: Destrument
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Scott
authors.forename: Simon T
authors.initials: ST
authors.lastname: Donell
authors.forename: Steve
authors.initials: S
authors.lastname: Fenwick
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Rowan
authors.forename: David A
authors.initials: DA
authors.lastname: Young
authors.forename: Ian M
authors.initials: IM
authors.lastname: Clark
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002417:Cattle; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D045726:Metalloproteases / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D055171:Nasal Cartilages / Q000187:drug effects* / Q000378:metabolism; D020370:Osteoarthritis, Knee; D011725:Pyridines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D011725:Pyridines; D034741:RNA, Small Interfering; D014404:Tubulin; C118739:entinostat; C012589:trichostatin A; D045726:Metalloproteases