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Rheumatology Advance Access published online on February 15, 2008
Rheumatology, doi:10.1093/rheumatology/ken003
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Anti-arthritic effects of combined treatment with histone deacetylase inhibitor and low-intensity ultrasound in the presence of microbubbles in human rheumatoid synovial cells

C. Nakamura1, I. Matsushita1, E. Kosaka1, T. Kondo2 and T. Kimura1

1Department of Orthopaedic Surgery and 2Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Toyama, Japan.

Correspondence to: T. Kimura, Department of Orthopaedic Surgery, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan. E-mail: tkimura{at}med.u-toyama.ac.jp


  Abstract

Objective. The therapeutic effects of histone deacetylase (HDAC) inhibitor combined with ultrasound (US) (1 MHz, 10% duty factor, 0.1 or 0.2 W/cm2) in RA synovial fibroblasts (RASFs) were examined.

Methods. RASFs were isolated from rheumatoid synovial tissues obtained from patients with RA during total knee arthroplasty. RASFs were treated with an HDAC inhibitor, trichostatin A (TSA), with or without US. Cell viability was estimated using the Trypan blue dye exclusion test and cell cycle was examined by flow cytometry using propidium iodide (PI) staining. Gene expression of cell cycle-related genes cyclin D, cyclin A, cyclin B and p21WAF1/Cip1 was analysed by semi-quantitative RT-PCR. Detection of apoptosis was examined by flow cytometry using annexin V-FITC and PI staining. Microarray analysis was carried out to profile gene expression of inflammation-related genes.

Results. Dose-dependent decreases in cell viability, cell cycle arrest and apoptosis in RASFs due to TSA were observed. US treatment in the presence of microbubbles increased cellular uptake, but did not induce cell cycle arrest or apoptosis. The combination of TSA and US modulated cell cycle-related gene expression and significantly decreased S phase cells and increased G2–M phase cells. US also further enhanced TSA-induced RASF apoptosis and regulated expression of inflammation-related genes.

Conclusions. HDAC inhibitor in combination with US effectively reduces cell viability and induces apoptosis in RASFs. The combination therapy could be useful to control synovial proliferation and inflammation, since US can be easily applied to targeted joints as local physiotherapy.

KEY WORDS: Rheumatoid, Synovial fibroblasts, Histone deacetylase inhibitor, Low-intensity ultrasound, Sonoporation

Submitted 11 October 2007; revised version accepted 2 January 2008.
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