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

Culley, Kirsty L., Hui, Wang, Barter, Matt J., Davidson, Rose K. ORCID: https://orcid.org/0000-0002-6624-4011, Swingler, Tracey E., Destrument, Auriane P. M., Scott, Jenny L., Donell, Simon T., Fenwick, Steve, Rowan, Andrew D., Young, David A. and Clark, Ian M. (2013) Class I histone deacetylase inhibition modulates metalloproteinase expression and blocks cytokine-induced cartilage degradation. Arthritis & Rheumatism, 65 (7). pp. 1822-1830. ISSN 0004-3591

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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.

Item Type:	Article
Faculty \ School:	Faculty of Science > School of Biological Sciences Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Nutrition and Preventive Medicine Faculty of Medicine and Health Sciences > Research Groups > Musculoskeletal Medicine Faculty of Medicine and Health Sciences > Research Centres > Lifespan Health Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User:	Pure Connector
Date Deposited:	25 Nov 2013 16:18
Last Modified:	13 Nov 2024 14:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/44907
DOI:	10.1002/art.37965

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