Session Type: Abstract Submissions (ACR)
Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease that affects synovial joints. A key characteristic of RA is hyperplasia of fibroblast-like synoviocytes (FLS) which develop a stable, auto-aggressive phenotype that augments tissue destruction. It is unknown how this phenotype is stably maintained, however epigenetic changes have been implicated. Histone acetylation is a major epigenetic mechanism (HDACs). The objective of the study is to determine the role of histone deacetylates (HDACs) in regulating the auto-aggressive phenotype of RA FLS
Real time-qPCR was used to compare levels of HDAC1-11 in RA compared with osteoarthritis (OA) FLS. Joint biopsies were co-stained with anti-HDAC1 and anti-fibroblast antibodies. HDAC1 and a non-targeting control (NTC) siRNA were transfected in vitro into RA FLS. Cell proliferation, migration and invasion after siRNA knockdown (KD) were assessed by using tritiated thymidine, a scratch assay and a matrigel invasion assay respectively. An Illumina BeadChip (47,000 transcripts) was used to analyse global gene expression changes after KD. The in vivo effect of HDAC1KD was investigated in a mouse model of collagen-induced arthritis (CIA) using in vivosiRNA. Clinical scores of CIA were measured daily (days 0-49) and the bones were analysed using a microCT scanner.
The mRNA levels of HDACs 1-11 are higher in RA compared to OA FLS, with HDAC1 levels showing a 4.2-fold increase (p=0.03, n=7-10). HDAC1KD reduced FLS proliferation (p=0.04, n=6), migration (p=0.01, n=6) and invasion (p=0.02, n=6) compared to the NTC. Cluster analysis of the microarrays (n=3) revealed significant changes in genes involved in apoptosis (p≤0.009, n=21), migration (p≤0.008, n=4) and proliferation (p≤0.009, n=9). In mice with CIA, HDAC1KD significantly inhibited joint inflammation (p=0.0001, n=10) and reduced bone erosion compared to the NTC.
Our data implicates HDAC1 in controlling the autoaggressive phenotype of FLS in RA and our data in murine inflammatory arthritis supports targeting HDACi as a potential therapy in RA.
J. M. Wilkinson,
A. G. Wilson,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/histone-deacetylase-one-contributes-to-the-auto-aggressive-phenotype-of-rheumatoid-arthritis/