title: Inhibition of CDK9 as a therapeutic strategy for inflammatory arthritis.
abstract: Rheumatoid arthritis is characterised by synovial inflammation and proliferation of fibroblast-like synoviocytes. The induction of apoptosis has long been proposed as a target for proliferative autoimmune diseases, and has further been shown to act as a successful treatment of experimental models of arthritis, such as collagen-induced arthritis. Here we examined the effects of specific oral small-molecule inhibitors of the transcription regulating cyclin-dependent kinase 9 on the development and progression of collagen-induced arthritis. DBA/1 mice were immunised with bovine collagen type II and treated orally with specific CDK9 inhibitors. The effects of CDK9 inhibition on RNA levels and protein expression, apoptosis induction, caspase activation and lymphocyte phenotype were further analysed. Mice showed a significant delay in disease onset and a reduction in disease severity following treatment with CDK9 inhibitors. Inhibiting CDK9 activity in peripheral blood mononuclear cells resulted in the loss of Mcl-1 expression at both the protein and RNA levels, along with a subsequent increase in apoptosis. CDK9 specific inhibitors may be a potential alternative treatment not only of cancer, but also for autoimmune- and inflammatory diseases. Taken together, these results show that transient inhibition of CDK9 induces apoptosis in leukocyte subsets and modulates the immune response.
authors: Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway.|Małopolska Centre of Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.
authors: Annelie
authors: A
authors: Hellvard
authors: Ingenium Pharmaceuticals GmbH, Fraunhoferstr. 13, 82152 Martinsried, Germany.
authors: Lutz
authors: L
authors: Zeitlmann
authors: Probiodrug AG, Weinbergweg 22, Biocenter, 06120 Halle/Saale, Germany.
authors: Ulrich
authors: U
authors: Heiser
authors: Probiodrug AG, Weinbergweg 22, Biocenter, 06120 Halle/Saale, Germany.
authors: Astrid
authors: A
authors: Kehlen
authors: Probiodrug AG, Weinbergweg 22, Biocenter, 06120 Halle/Saale, Germany.
authors: André
authors: A
authors: Niestroj
authors: Ingenium Pharmaceuticals GmbH, Fraunhoferstr. 13, 82152 Martinsried, Germany.|Probiodrug AG, Weinbergweg 22, Biocenter, 06120 Halle/Saale, Germany.
authors: Hans-Ulrich
authors: HU
authors: Demuth
authors: Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.
authors: Joanna
authors: J
authors: Koziel
authors: Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway.
authors: Nicolas
authors: N
authors: Delaleu
authors: Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.|University of Louisville School of Dentistry, Department of Oral Immunology and Infectious Diseases, Louisville, KY, USA.
authors: Jan Potempa
authors: Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway.|Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: Piotr
authors: P
authors: Mydel
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D024043:Collagen Type II / Q000008:administration & dosage; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D020869:Gene Expression Profiling; D007155:Immunologic Factors / Q000008:administration & dosage*; D008214:Lymphocytes / Q000502:physiology; D008811:Mice, Inbred DBA; D020543:Proteome / Q000032:analysis; D016896:Treatment Outcome
chemical_list: D024043:Collagen Type II; D004791:Enzyme Inhibitors; D007155:Immunologic Factors; D020543:Proteome; C467972:Cdk9 protein, mouse; D042863:Cyclin-Dependent Kinase 9