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Therapy
Local steroid activation is a critical mediator of the anti-inflammatory actions of therapeutic glucocorticoids
  1. Chloe Fenton1,2,
  2. Claire Martin1,
  3. Rachel Jones1,3,
  4. Adam Croft2,
  5. Joana Campos2,
  6. Amy J Naylor2,4,
  7. Angela E Taylor1,5,
  8. Myriam Chimen2,6,
  9. Mark Cooper7,
  10. Gareth G Lavery1,3,5,
  11. Karim Raza2,8,
  12. Rowan S Hardy2,3,6
  1. 1 Institute for Metabolism and Systems Research, University of Birmingham, Birmingham, UK
  2. 2 Research into Inflammatory Arthritis Centre, Versus Arthritis, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
  3. 3 MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research, University of Birmingham Edgbaston Campus, Birmingham, UK
  4. 4 Centre for Translational Inflammation Research, University of Birmingham, Birmingham, UK
  5. 5 Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK
  6. 6 Institute for Clinical Sciences, University of Birmingham, Birmingham, UK
  7. 7 ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia
  8. 8 Rheumatology, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK
  1. Correspondence to Dr Rowan S Hardy, IMSR, University of Birmingham, Birmingham B15 2TT, UK; R.Hardy{at}bham.ac.uk

Abstract

Objectives The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a well-characterised role in the metabolism and activation of endogenous glucocorticoids (GCs). However, despite its potent upregulation at sites of inflammation, its role in peripheral metabolism and action of therapeutic GCs remains poorly understood. We investigated the contribution of 11β-HSD1 to the anti-inflammatory properties of the active GC corticosterone, administered at therapeutic doses in murine models of polyarthritis.

Methods Using the tumour necrosis factor-tg and K/BxN serum-induced models of polyarthritis, we examined the anti-inflammatory properties of oral administration of corticosterone in animals with global, myeloid and mesenchymal targeted transgenic deletion of 11β-HSD1. Disease activity and joint inflammation were scored daily. Joint destruction and measures of local and systemic inflammation were determined by histology, micro-CT, quantitative RT-PCR, fluorescence activated cell sorting and ELISA.

Results Global deletion of 11β-HSD1 resulted in a profound GC resistance in animals receiving corticosterone, characterised by persistent synovitis, joint destruction and inflammatory leucocyte infiltration. This was partially reproduced with myeloid, but not mesenchymal 11β-HSD1 deletion, where paracrine GC signalling between cell populations was shown to overcome targeted deletion of 11β-HSD1.

Conclusions We identify an entirely novel component of therapeutic GC action, whereby following their systemic metabolism, they require peripheral reactivation and amplification by 11β-HSD1 at sites of inflammation to deliver their anti-inflammatory therapeutic effects. This study provides a novel mechanistic understanding of the anti-inflammatory properties of therapeutic GCs and their targeting to sites of inflammation in polyarthritis.

  • arthritis
  • arthritis
  • experimental
  • glucocorticoids
  • inflammation
  • synovitis
https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/annrheumdis-2020-218493

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    Footnotes

    • Handling editor Josef S Smolen

    • Twitter @joanadcampos

    • Correction notice This article has been corrected since it published Online First. Figures 3 and 4 have been corrected.

    • Contributors CF carried out experiments with support from CM, RJ, AC, AJN, AET, MC, JC and RH. RH, KR, GGL and MC conceived and supervised the project. RH wrote the manuscript. All authors discussed the results and contributed to the final manuscript.

    • Funding This research was supported by Versus Arthritis grants (reference: 19859 and 20843).

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval Procedures were performed under guidelines by the Animal (Scientific Procedures) Act 1986 in accordance with the project licence (P51102987) and approved by the Birmingham Ethical Review Subcommittee (BERSC).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as online supplementary information. Data are available on reasonable request from Dr Hardy. Reuse of data is not permitted by a third party without authorisation.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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