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

Lookup NU author(s): Dr Matthew Barter, Dr Auriane Destrument, Jenny Scott, Emeritus Professor Drew Rowan


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ObjectiveTo 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. MethodsA 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. ResultsSystemically 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. ConclusionInhibition 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 metadata

Author(s): Culley KL, Hui W, Barter MJ, Davidson RK, Swingler TE, Destrument APM, Scott JL, Donell ST, Fenwick S, Rowan AD, Young DA, Clark IM

Publication type: Article

Publication status: Published

Journal: Arthritis & Rheumatism

Year: 2013

Volume: 65

Issue: 7

Pages: 1822-1830

Print publication date: 02/07/2013

ISSN (print): 0004-3591

ISSN (electronic): 1529-0131

Publisher: John Wiley & Sons, Inc.


DOI: 10.1002/art.37965


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Funder referenceFunder name
Biotechnology and Biological Sciences Research Council
JGW Patterson Foundation
Smith & Nephew (through a BBSRC CASE studentship)
Newcastle University Hospitals Special Trustees, UK
NIHR Biomedical Research Centre in Ageing and Age Related Disease
Wear Comprehensive Local Research Network
19485Arthritis Research UK
18726Arthritis Research UK