The glucocorticoid receptor in skeletal health and disease: insights from targeted knockout mice

in Journal of Endocrinology
Authors:
Eugenie Macfarlane Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia

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https://orcid.org/0000-0003-3608-3285
,
Hong Zhou Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia

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https://orcid.org/0000-0001-5899-9660
, and
Markus J Seibel Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia
Department of Endocrinology and Metabolism, Concord Repatriation General Hospital, Sydney, Australia

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https://orcid.org/0000-0002-2701-378X

Correspondence should be addressed to E Macfarlane: eugenie.macfarlane@sydney.edu.au

This paper forms part of a special collection produced in collaboration with the Endocrine Society of Australia. The guest editors for this section were Timothy Cole and Bu Yeap.

DOI:
https://doi.org/10.1530/JOE-23-0399
Volume/Issue:
Volume 261: Issue 2
Article Type:
Review Article
Article ID:
e230399
Online Publication Date:
28 Mar 2024
Copyright:
© the author(s) 2024
Collections:
Endocrine Society of Australia special collection
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Glucocorticoids are steroid hormones, secreted by the adrenals to regulate a range of metabolic, immunologic, and homeostatic functions. Due to their potent anti-inflammatory effects, synthetic glucocorticoids are widely used to treat inflammatory disorders. However, their use especially at high doses and over the long-term is associated with several unwanted side effects that compromises their intended use (e.g. glucocorticoid-induced osteoporosis and/or diabetes, myopathy, and skin atrophy). Both endogenous and synthetic glucocorticoids exert their effects through the glucocorticoid receptor, a transcription factor present in nearly all nucleated cells. Glucocorticoid receptor knockout mouse models have proved to be valuable tools in understanding how glucocorticoids contribute to skeletal health and disease. These models, described in this review, have helped to establish that the effects of glucocorticoids on the skeleton are multifaceted, cell specific and concentration dependent. Intriguingly, while endogenous glucocorticoids are essential for bone formation, high-dose exogenous glucocorticoids may induce bone loss. Additionally, the actions of endogenous glucocorticoids vary greatly depending on the disease microenvironment. For example, endogenous glucocorticoids have predominately beneficial anti-inflammatory effects in rheumatoid arthritis, but detrimental actions in osteoarthritis by driving cartilage loss and abnormal bone formation. Studies in tissue-specific knockout models provide important insights that will aid the development of new glucocorticoid therapeutics that can specifically target certain cell types to minimise unwanted effects from current glucocorticoid therapy.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© the author(s) 2024
Article ID:
e230399
Article Type:
Review Article
Received Date:
14 Dec 2023
Accepted Date:
07 Mar 2024
Print Publication Date:
01 May 2024
Online Publication Date:
28 Mar 2024
Keywords:
glucocorticoid receptor; glucocorticoids; knockout mice; skeletal disease; skeletal development; bone loss; fracture; arthritis

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