Inhibition of CDK9 as a therapeutic strategy for inflammatory arthritis.

Annelie Hellvard,Ulrich Heiser,Nicolas Delaleu,Astrid Kehlen,Piotr Mydel,Lutz Zeitlmann,Joanna Koziel,Hans-Ulrich Demuth,Jan Potempa Jan Potempa,André Niestroj

doi:10.1038/srep31441

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.

Highlights

Because neither of these compounds discriminates between CDKs involved in the cell cycle and those involved in transcriptional regulation, these studies did not examine the ability of CDK9 to inhibition transcription or its subsequent effect on apoptosis
Treating collagen-induced arthritis (CIA) with flavopiridol, which inhibits CDK1, 2, 4, 6, 7, and 9, has proven to be a successful approach[14], we hypothesised that CDK9 is the key target of flavopiridol in the treatment of RA
When we treated CIA mice with specific CDK9 inhibitors, we observed a marked improvement in the clinical signs of arthritis

Summary

Introduction

Because neither of these compounds discriminates between CDKs involved in the cell cycle and those involved in transcriptional regulation, these studies did not examine the ability of CDK9 to inhibition transcription or its subsequent effect on apoptosis. Targeting CDK9 is a novel method of controlling immune responses without affecting the cell cycle. Garcia-Cuellar et al recently showed that the CDK9 inhibitors PC585 and PC579 are efficient suppressors of mixed-lineage leukemia proliferation and that CDK9 inhibition increase the survival in a murine mixed-lineage leukemia model[15]. No study has yet examined whether specific CDK9 inhibitors have an effect on RA. The aim of the present study was to examine the effects of two highly specific CDK9 inhibitors in a murine model of collagen-induced arthritis (CIA)

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