title: Histone deacetylase 1 regulates tissue destruction in rheumatoid arthritis.
abstract: Emerging evidence implicates epigenetic mechanisms in the pathogenesis of rheumatoid arthritis (RA). In this study, we have investigated the role of histone deacetylase (HDAC) enzymes in RA synovial fibroblasts (RASFs), a key cellular mediator of cartilage and bone destruction and determined effects of HDAC1 inhibition on both RASF phenotype in vitro, and joint inflammation and damage in the collagen-induced arthritis (CIA) model. Expression of HDACs 1-11 messenger ribonucleic acid (mRNA) was compared between RASFs and osteoarthritic synovial fibroblast (OASFs) using quantitative polymerase chain reaction. HDAC1 expression in RASFs was inhibited using small interfering RNA (siRNA) technology to assess effects on invasiveness, migration, proliferation and apoptosis. Effects of HDAC1 knockdown (KD) on the transcriptome were assessed using gene microarrays. The effects of siRNA-mediated HDAC(KD) on clinical scores, tissue inflammation and damage were assessed on CIA up to 47 days following immunization. Expression of HDAC1 was significantly higher in RASFs than OASFs. HDAC1(KD) resulted in reduced proliferation, invasion and migration in vitro and transcriptome profiling revealed effects on expression of genes regulating proliferation migration and inflammation. Furthermore, inhibition of HDAC1 in CIA resulted in reduced joint swelling, cartilage and bone damage and lower tumor necrosis factor in joint tissue. These results implicate HDAC1 as an important mediator of tissue damage in RA and support the potential therapeutic utility of inhibitors of this enzyme.
authors.affiliation: Department of Infection and Immunity, University of Sheffield, Sheffield S10 2RX, UK and.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hawtree
authors.affiliation: Department of Infection and Immunity, University of Sheffield, Sheffield S10 2RX, UK and.
authors.forename: Munitta
authors.initials: M
authors.lastname: Muthana
authors.affiliation: Academic Unit of Bone Metabolism, University of Sheffield, Sheffield S10 2RX, UK and.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Wilkinson
authors.affiliation: Department of Infection and Immunity, University of Sheffield, Sheffield S10 2RX, UK and.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Akil
authors.affiliation: Department of Infection and Immunity, University of Sheffield, Sheffield S10 2RX, UK and Conway Institute, Belfield Campus, University College Dublin, Dublin 4, Ireland gerry.wilson@ucd.ie.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Wilson
mesh_terms: D000818:Animals; D017209:Apoptosis; D001169:Arthritis, Experimental / Q000235:genetics / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D056284:Histone Deacetylase 1 / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D010003:Osteoarthritis / Q000235:genetics / Q000473:pathology*; D013583:Synovial Membrane / Q000201:enzymology / Q000473:pathology
chemical_list: C110550:HDAC1 protein, human; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1