Class I Histone Deacetylase Inhibition Modulates Metalloproteinase Expression and Blocks Cytokine‐Induced Cartilage Degradation. Issue 7 (2nd July 2013)

• Record Type: Journal Article
• Authors: Culley, Kirsty L.; Hui, Wang; Barter, Matt J.; Davidson, Rose K.; Swingler, Tracey E.; Destrument, Auriane P. M.; Scott, Jenny L.; Donell, Simon T.; Fenwick, Steve; Rowan, Andrew D.; Young, David A.; Clark, Ian M.
• Is Part Of: Arthritis and rheumatism. Volume 65:Issue 7(2013:Jul.)
• Page Start: 1822
• Page End: 1830
• Publication Date: 2013-07-02
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; Arthritis -- Periodicals; Rheumatic Diseases -- Periodicals; Rhumatisme -- Périodiques; Arthrite -- Périodiques; 616.72
• DOI: 10.1002/art.37965
• Languages: English
• ISSNs: 0004-3591

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="art37965-sec-0001" sec-type="section"> <title>Objective</title> <p>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.</p> </sec> <sec id="art37965-sec-0002" sec-type="section"> <title>Methods</title> <p>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.</p> </sec> <sec id="art37965-sec-0003" sec-type="section"> <title>Results</title> <p>Systemically administered TSA protected cartilage in the DMM model. TSA, valproic acid, and MS‐275 repressed cytokine‐induced <italic>MMP1</italic> and <italic>MMP13</italic> expression in HACs. Knockdown of each class I HDAC diminished interleukin‐1–induced <italic>MMP13</italic> expression. All of the HDAC inhibitors prevented degradation of BNC, in which TSA and MS‐275 repressed cytokine‐induced <italic>MMP</italic> expression.</p> </sec> <sec id="art37965-sec-0004" sec-type="section"> <title>Conclusion</title> <p>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.</p> </sec> </abstract>