Increased activity and expression of histone deacetylase 1 in relation to tumor necrosis factor-alpha in synovial tissue of rheumatoid arthritis

Abstract

IntroductionThe purpose of this study was to investigate the profile of histone deacetylase (HDAC) expression in the synovial tissue of rheumatoid arthritis (RA) compared with that of normal control and osteoarthritis (OA), and to examine whether there is a link between HDAC activity and synovial inflammation.MethodsHDAC activity and histone acetyltransferase (HAT) activity were determined in nuclear extracts of total synovial tissue surgically obtained from normal, OA and RA joints. The level of cytoplasmic tumor necrosis factor a (TNFα) fraction was measured by ELISA. Total RNA of synovial tissue was used for RT-PCR of HDAC1-8. In synovial fibroblasts from RA (RASFs), the effects of TNFα on nuclear HDAC activity and class I HDACs (1, 2, 3, 8) mRNA expressions were examined by quantitative real-time PCR. The protein expression and distribution of class I HDACs were examined by Western blotting.ResultsNuclear HDAC activity was significantly higher in RA than in OA and normal controls and correlated with the amount of cytoplasmic TNFα. The mRNA expression of HDAC1 in RA synovial tissue was higher than in OA and normal controls, and showed positive correlation with TNFα mRNA expression. The protein level of nuclear HDAC1 was higher in RA synovial tissue compared with OA synovial tissue. Stimulation with TNFα significantly increased the nuclear HDAC activity and HDAC1 mRNA expression at 24 hours and HDAC1 protein expression at 48 hours in RASFs.ConclusionsOur results showed nuclear HDAC activity and expression of HDAC1 were significantly higher in RA than in OA synovial tissues, and they were upregulated by TNFα stimulation in RASFs. These data might provide important clues for the development of specific small molecule HDAC inhibitors.

Histone deacetylases (HDAC) in physiological and pathological bone remodelling

“…expression of HDAC 1 was correlated with expression of inflammatory cytokine TNF-α [29]. More recent studies have confirmed a role for HDAC 1 in the inflammatory tissue destruction in RA.…”

“…The 18 HDAC enzymes are widely expressed in tissues throughout the body and deacetylate both histone and non-histone proteins, making it challenging to determine the precise mechanism of action of different HDACi. Despite the ubiquitous nature of class I HDACs, differences in expression of these enzymes have been observed in a number of malignancies and also in rheumatoid arthritis (RA) [26][27][28][29]. This review focuses on HDACs and…”

1H NMR-based metabolomic analysis for identifying serum biomarkers to evaluate methotrexate treatment in patients with early rheumatoid arthritis

“…Although well proven, it is recognized that there are large individual differences in the optimal dose of MTX for RA patients (5). The reasons for those individual differences are thought to be different concentrations of intracellular MTX-polyglutamates (MTX-PGs) and different enzyme activities at MTX-active sites (6 cytokines and other mediators of inflammation, such as tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10), may also correlate with the efficacy of MTX (7,8). However, rapid clinical assays to measure these such as MTX-PGs, enzyme and cytokines are technically difficult and not available in most clinical facilities (9,10).…”

Regulated Transcription of Human Matrix Metalloproteinase 13 (MMP13) and Interleukin-1β (IL1B) Genes in Chondrocytes Depends on Methylation of Specific Proximal Promoter CpG Sites

“…Moreover, only a few reports have addressed how methylation of individual CpG sites influences the promoter activity of a specific gene (6,10,11), and the relative contributions of the methylation status of each individual CpG site to the transcriptional regulation of a given gene in vivo remain largely unexplored. In addition, although epigenetic gene regulation has been broadly investigated in other contexts, little is known about the specific impact of this mechanism of gene control in musculoskeletal diseases (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29).…”