Class I histone deacetylase inhibition modulates metalloproteinase expression and blocks cytokine-induced cartilage degradation

Kirsty L. Culley, Wang Hui, Matt J. Barter, Rose K. Davidson, Tracey E. Swingler, Auriane P. M. Destrument, Jenny L. Scott, Simon T. Donell, Steve Fenwick, Andrew D. Rowan, David A. Young, Ian M. Clark

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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.
Original languageEnglish
Pages (from-to)1822-1830
Number of pages9
JournalArthritis & Rheumatism
Volume65
Issue number7
DOIs
Publication statusPublished - 1 Jul 2013

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