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K A Reedquist

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Histone deacetylases in RA: epigenetics and epiphenomena
Grabiec, A.M.; Reedquist, K.A.
Published in:
Arthritis Research & Therapy
DOI:
10.1186/ar3137
Link to publication
Citation for published version (APA):
Grabiec, A. M., & Reedquist, K. A. (2010). Histone deacetylases in RA: epigenetics and epiphenomena. Arthritis
Research & Therapy, 12(5), 142. https://doi.org/10.1186/ar3137
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Download date: 02 Jul 2019
In the previous issue of Arthritis Research & Th erapy, 
Kawabata and colleagues [1] examined the activity and 
expression of histone deacetylases (HDACs) in the syno-
vial tissue of patients with rheumatoid arthritis (RA) in 
relation to local tumor necrosis factor-alpha (TNFα) 
production. Th e authors found that total HDAC activity 
was increased in RA synovial tissue compared with 
osteo arthritis (OA) disease control and normal control 
tissues. Expression of HDAC1 was signifi cantly elevated 
in RA among HDACs examined. Similarly, HDAC1 
expres sion was elevated in RA fi broblast-like synovio-
cytes (FLSs) compared with OA FLSs. Both total synovial 
HDAC activity and HDAC1 expression were associated 
with increased TNFα production, and in attempting to 
understand the cellular basis of this relationship, the 
authors found that TNFα stimulation of RA FLSs led to 
transient increases in cellular HDAC activity and HDAC1 
expression. Th is report is noteworthy for the eff orts of 
the authors to resolve apparent discrepancies between 
their data and the published literature [2] and for the 
resulting new questions regarding how HDACs might 
contribute to RA.
Histone acetyltransferases (HATs) and HDACs recipro-
cally regulate the acetylation status of cellular proteins. 
Acetylation of histones promotes unwinding of com-
pacted chromatin and allows access of transcription 
factors to gene promoter regions, and by extension, 
changes in relative HAT/HDAC activity would be 
expected to infl uence the sensitivity of cellular gene 
trans cription in response to extracellular stimuli. Th is 
epigenetic mechanism of gene regulation has been 
suggest ed to contribute to pathology in complex 
immune-mediated infl ammatory diseases, such as 
chronic obstructive pulmonary disease (COPD) and 
asthma, in which depressed HDAC activity at the site of 
infl ammation, especially in macrophages, is associated 
with disease severity and infl ammatory cytokine produc-
tion and contributes to glucocorticoid resistance [3]. An 
initial examination of HAT and HDAC activity in RA 
synovial tissue [2] painted a picture suggesting many 
similarities with COPD and asthma [4], noting depressed 
synovial HDAC activity in RA tissue compared with OA 
and normal donor tissues, particularly in regard to 
HDAC1 and HDAC2 expression. Th is initial study 
suggests that decreased HDAC activity may contribute to 
pathology in RA (and render RA patients resistant to 
future treatment with HDAC inhibitors) [2]. Kawabata 
and colleagues, in contrast, argue that increased HDAC1 
activity may contribute to RA and represent a new 
therapeutic target [1].
Th e studies conducted by both groups are technically 
impeccable, ruling out many trivial explanations for 
discordant results. However, Kawabata and colleagues 
noted that none of the patients they examined was 
treated with TNFα-blocking biologicals and that synovial 
TNFα production signifi cantly correlated with HDAC 
activity and HDAC1 expression. In contrast, a substantial 
Abstract
Reduced synovial expression of histone deacetylases 
(HDACs) is proposed to contribute to pathology 
in rheumatoid arthritis (RA) by enhancing histone-
dependent access of transcription factors to promoters 
of infl ammatory genes. In the previous issue of Arthritis 
Research & Therapy, Kawabata and colleagues provided 
independent evidence that HDAC activity is increased 
in the synovium and fi broblast-like synoviocytes (FLSs) 
of patients with RA and is paralleled by increased 
HDAC1 expression and synovial tumor necrosis factor-
alpha (TNFα) production. Remarkably, stimulation of RA 
FLSs with TNFα specifi cally increases HDAC activity and 
HDAC1 expression, suggesting that changes in synovial 
HDAC activity and expression may be secondary to 
local infl ammatory status.
© 2010 BioMed Central Ltd
Histone deacetylases in RA: epigenetics 
and epiphenomena
Aleksander M Grabiec and Kris A Reedquist*
See related research by Kawabata et al., http://arthritis-research.com/content/12/4/R133
E D I TO R I A L
*Correspondence: k.a.reedquist@amc.uva.nl
Division of Clinical Immunology and Rheumatology, Academic Medical Center, 
University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Grabiec and Reedquist Arthritis Research & Therapy 2010, 12:142 
http://arthritis-research.com/content/12/5/142
© 2010 BioMed Central Ltd
number of the RA patients studied by Huber and 
colleagues [2] received TNFα-blocking therapies, raising 
the possibility that TNFα drives HDAC expression and 
activity. Although independent analyses of larger patient 
cohorts and prospective clinical studies are needed to 
substantiate this idea in vivo, initial in vitro experiments 
showing that TNFα stimulation induces RA FLS HDAC 
activity and HDAC1 expression [1] are compelling.
Several aspects of these two studies deserve further 
exploration. Variation in HDAC activity and expression 
between RA and non-infl ammatory OA observed by 
both groups is modest, and little is known about the 
magnitude of fl uctuation in cellular HDAC activity 
suffi  cient to modify infl ammatory responses. Analyses of 
mice expressing only single alleles of specifi c HDACs in 
experimental arthritis models may be useful in answering 
this question. It is also uncertain whether altered synovial 
HDAC activity infl uences therapeutic strategies targeting 
the balance of synovial protein acetylation, as HDAC 
inhibitors are uniformly eff ective in animal models of RA 
[5] and demonstrate anti-infl ammatory properties in RA 
FLSs [6], synovial macrophages, and synovial biopsy 
explants [7]. Kawabata and colleagues also provide 
evidence strengthening the hypothesis that HDACs are 
intimately involved in infl ammatory signal transduction 
pathways in RA. Th e timing of changes in HDAC activity 
and expression following TNFα stimulation corresponds 
with the involvement of signaling proteins required for 
FLS cytokine responses, including nuclear factor-kappa-B 
(NF-κB) p65, JAK/STAT (Janus kinase/signal trans ducer 
and activator of transcription) signaling components, 
AP-1 (activator protein-1), and p53. Th ese proteins are 
regulated by reversible acetylation [5], and the bio-
chemical eff ects of acetylation (regulation of protein 
activa tion, localization, stability, and target specifi city) 
are as diverse as those regulated by phosphorylation [8]. 
Indeed, recent evidence has demonstrated that, in trans-
formed RA FLSs, HDAC inhibitors prevent activation of 
NF-κB p65 [9].
Finally, while HDAC1 is the most prominent Class I/II 
HDAC in RA synovial tissue and FLS [1,6], silencing of 
either HDAC1 or HDAC2 have similar eff ects on FLS 
survival and proliferation [6]. Th is may suggest either 
that there are numerous redundancies in HDAC target 
specifi city, or that bulk HDAC activity is most relevant to 
infl ammatory and pro-survival gene expression in RA, 
important in considering whether inhibition of specifi c 
HDACs will be needed in therapeutic strategies. 
Reaching a consensus on the expression and activity of 
new biological targets in RA is a critical step in the 
evaluation of their role and therapeutic potential. 
However, as exemplifi ed by the burst of recent research 
on HDAC biology in RA, the initial disparate results and 
conclusions are what accelerate our drive to spark the 
most intriguing questions and reach this consensus.
Abbreviations
COPD, chronic obstructive pulmonary disease; FLS, fi broblast-like synoviocyte; 
HAT, histone acetyltransferase; HDAC, histone deacetylase; NF-κB, nuclear 
factor-kappa-B; OA, osteoarthritis; RA, rheumatoid arthritis; TNFα, tumor 
necrosis factor-alpha.
Competing interests
The authors declare that they have no competing interests.
Published: 11 October 2010
References
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8. Glozak MA, Sengupta N, Zhang X, Seto E: Acetylation and deacetylation of 
non-histone proteins. Gene 2005, 363:15-23.
9. Choo QY, Ho PC, Tanaka Y, Lin HS: Histone deacetylase inhibitors MS-275 
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doi:10.1186/ar3137
Cite this article as: Grabiec AM, Reedquist KA: Histone deacetylases in RA: 
epigenetics and epiphenomena. Arthritis Research & Therapy 2010, 12:142.
Grabiec and Reedquist Arthritis Research & Therapy 2010, 12:142 
http://arthritis-research.com/content/12/5/142
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