title: Differentially expressed epigenome modifiers, including aurora kinases A and B, in immune cells in rheumatoid arthritis in humans and mouse models.
abstract: OBJECTIVE
  To identify epigenetic factors that are implicated in the pathogenesis of rheumatoid arthritis (RA), and to explore the therapeutic potential of the targeted inhibition of these factors.
  
  
  METHODS
  Polymerase chain reaction (PCR) arrays were used to investigate the expression profile of genes that encode key epigenetic regulator enzymes. Mononuclear cells from RA patients and mice were monitored for gene expression changes, in association with arthritis development in murine models of RA. Selected genes were further characterized by quantitative reverse transcription-PCR, Western blot, and flow cytometry methods. The targeted inhibition of the up-regulated enzymes was studied in arthritic mice.
  
  
  RESULTS
  A set of genes with arthritis-specific expression was identified by the PCR arrays. Aurora kinases A and B, both of which were highly expressed in arthritic mice and treatment-naive RA patients, were selected for detailed analysis. Elevated aurora kinase expression was accompanied by increased phosphorylation of histone H3, which promotes proliferation of T lymphocytes. Treatment with VX-680, a pan-aurora kinase inhibitor, promoted B cell apoptosis, provided significant protection against disease onset, and attenuated inflammatory reactions in arthritic mice.
  
  
  CONCLUSIONS
  Arthritis development is accompanied by changes in expression of a number of epigenome-modifying enzymes. Drug-induced down-regulation of the aurora kinases, among other targets, seems to be sufficient to treat experimental arthritis. Development of new therapeutics that target aurora kinases can potentially improve RA management.
authors: Rush University Medical Center, Chicago, IL, USA. Tibor_Rauch@rush.edu
authors: Tibor T
authors: TT
authors: Glant
authors: Timea
authors: T
authors: Besenyei
authors: András
authors: A
authors: Kádár
authors: Júlia
authors: J
authors: Kurkó
authors: Beata
authors: B
authors: Tryniszewska
authors: János
authors: J
authors: Gál
authors: Györgyi
authors: G
authors: Soós
authors: Zoltán
authors: Z
authors: Szekanecz
authors: Gyula
authors: G
authors: Hoffmann
authors: Joel A
authors: JA
authors: Block
authors: Robert S
authors: RS
authors: Katz
authors: Katalin
authors: K
authors: Mikecz
authors: Tibor A
authors: TA
authors: Rauch
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001169:Arthritis, Experimental / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000235:genetics; D064127:Aurora Kinases; D001402:B-Lymphocytes / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects; D015854:Up-Regulation; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D064127:Aurora Kinases; D006657:Histones; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
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