Identification of Gene Signatures for Prednisolone-Induced Metabolic Dysfunction in Collagen-Induced Arthritic Mice

Abstract

Background: Prednisolone is a potent anti-inflammatory glucocorticoid (GC) but chronic use is hampered by metabolic side effects. Little is known about the long-term effects of GCs on gene-expression in vivo during inflammation. Aim: Identify gene signatures underlying prednisolone-induced metabolic side effects in a complex in vivo inflammatory setting after long-term treatment. Materials & methods: We performed whole-genome expression profiling in liver and muscle from arthritic and nonarthritic mice treated with several doses of prednisolone for 3 weeks and used text-mining to link gene signatures to metabolic pathways. Results: Prednisolone-induced gene signatures were highly tissue specific. We identified a short-list of genes significantly affected by both prednisolone and inflammation in liver and involved in glucose and fatty acid metabolism. For several of these genes the association with GCs is novel. Conclusion: The identified gene signatures may provide useful starting points for the development of GCs with a better safety profile.

Original submitted 2 September 2013; Revision submitted 3 January 2014

KEYWORDS::

• collagen-induced arthritis mouse model
• glucocorticoids
• insulin sensitivity
• metabolic side effects
• prednisolone
• transcriptomics
• whole-genome expression profiling

Financial & competing interests disclosure

This research was performed within the framework of project T1–106 of the Dutch Top Institute Pharma. The effort of S Ellero-Simatos was supported by the research program of the Netherlands Metabolomics Centre (NMC), part of The Netherlands Genomics Initiative/Netherlands Organization for Scientific Research. WWM Fleuren is supported by The Netherlands eScience Center. S Bauerschmidt and WHA Dokter were previously employed by Merck Sharpe & Dohme. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This research was performed within the framework of project T1–106 of the Dutch Top Institute Pharma. The effort of S Ellero-Simatos was supported by the research program of the Netherlands Metabolomics Centre (NMC), part of The Netherlands Genomics Initiative/Netherlands Organization for Scientific Research. WWM Fleuren is supported by The Netherlands eScience Center. S Bauerschmidt and WHA Dokter were previously employed by Merck Sharpe & Dohme. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.