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The multiple facets of glucocorticoid action in rheumatoid arthritis

Nature Reviews Rheumatology volume 8, pages 645–655 (2012)Cite this article

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Abstract

Glucocorticoids have potent anti-inflammatory effects and have been used to treat patients with rheumatoid arthritis for more than 60 years. However, severe adverse effects of glucocorticoid treatment, including loss of bone mass and increased risk of fractures, are common. Data from studies of glucocorticoid-mediated gene regulation, which utilized conditional knockout mice in animal models of arthritis or glucocorticoid-induced osteoporosis, have substantially increased our understanding of the mechanisms by which glucocorticoids act via the glucocorticoid receptor. Following glucocorticoid binding, the receptor regulates gene expression either by interacting with DNA-bound transcription factors as a monomer or by binding directly to DNA as a dimer. In contrast to the old hypothesis that transrepression mechanisms involving monomeric glucocorticoid receptor actions were responsible for the anti-inflammatory effects of glucocorticoids, whereas dimeric glucocorticoid receptor binding resulted in adverse effects, data from animal models have shown that the anti-inflammatory and adverse effects of glucocorticoids are mediated by both monomeric and dimeric glucocorticoid receptor binding. This improved knowledge of the molecular mechanisms that underlie the beneficial and adverse effects of glucocorticoid therapy might lead to the development of rationales for novel glucocorticoid receptor ligands that could potentially have anti-inflammatory efficacy without adverse effects on bone.

Key Points

  • Despite having severe adverse effects on bone, glucocorticoids have been used to treat patients with rheumatoid arthritis for more than 60 years

  • Glucocorticoids are powerful anti-inflammatory agents that act via the glucocorticoid receptor

  • The glucocorticoid receptor can regulate gene expression as a homodimer that binds directly to DNA or as a monomer that interacts with DNA-bound transcription factors

  • In animal models of arthritis, the anti-inflammatory activity of glucocorticoids requires glucocorticoid receptor dimerization, and in one model requires this dimerization on T cells

  • Deleterious effects of glucocorticoids on bone, such as inhibition of osteoblast function and induction of osteoclastogenesis, might be partly the result of actions of the glucocorticoid receptor monomer

  • Selective glucocorticoid receptor agonists that modulate glucocorticoid receptor function in specific tissues could have similar anti-inflammatory activity to traditional glucocorticoids without their associated adverse effects

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Figure 1: Binding of glucocorticoid receptor monomers and dimers to DNA.
Figure 2: Mechanisms of regulation of gene transcription by activated glucocorticoid receptors.
Figure 3: Cell-type-specific actions of glucocorticoids in the inflamed joint.
Figure 4: Glucocorticoid actions on bone.
Figure 5: Criteria for novel SGRMs.

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (DFG Tu220/3, Tu220/6 within the Priority Program “Immunobone” SPP 1486; J. Tuckermann), the Boehringer Ingelheim Stiftung (J. Tuckermann), the Leibniz Graduate School of Ageing of the Fritz Lipmann Institute (U. Baschant), NIH grants K24-AR04884-06 and R01 AR043052 (N. E. Lane) and Endowed for Aging from University of California, Davis (N. E. Lane).

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Authors and Affiliations

  1. Leibniz Institute for Age Research, Fritz Lipmann Institute, Beutenbergstraße 11, D-07745, Jena, Germany

    Ulrike Baschant

  2. University of California at Davis School of Medicine, 4610 X Street, Sacramento, 95817, CA, USA

    Nancy E. Lane

  3. Institute of General Zoology and Endocrinology, University of Ulm, Zentrum für Biomedizinische Forschung (ZBF), Helmholtzstraße 8/1, 89081, Ulm, Germany

    Jan Tuckermann

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  1. Ulrike Baschant
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  2. Nancy E. Lane
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U. Baschant and J. Tuckermann researched the data, wrote the article, provided a substantial contribution to discussions of the content and reviewed and edited the manuscript before submission. N. E. Lane wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Jan Tuckermann.

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The authors declare no competing financial interests.

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Baschant, U., Lane, N. & Tuckermann, J. The multiple facets of glucocorticoid action in rheumatoid arthritis. Nat Rev Rheumatol 8, 645–655 (2012). https://doi.org/10.1038/nrrheum.2012.166

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