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

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...

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Published in:Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2013-07, Vol.65 (7), p.1822-1830
Main 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.
Format: Article
Language:English
Subjects:
Animals
Benzamides - pharmacology
Cartilage
Cattle
Cell Line, Tumor
Cells, Cultured
Chondrocytes - drug effects
Chondrocytes - metabolism
Cytokines
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
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Summary: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.
ISSN:0004-3591
2326-5191
1529-0131
2326-5205
DOI:10.1002/art.37965