Journey through discovery of 75 years glucocorticoids: evolution of our knowledge of glucocorticoid receptor mechanisms in rheumatic diseases
Open accessAbstract
For three-quarters of a century, glucocorticoids (GCs) have been used to treat rheumatic and autoimmune diseases. Over these 75 years, our understanding of GCs binding to nuclear receptors, mainly the glucocorticoid receptor (GR) and their molecular mechanisms has changed dramatically. Initially, in the late 1950s, GCs were considered important regulators of energy metabolism. By the 1970s/1980s, they were characterised as ligands for hormone-inducible transcription factors that regulate many aspects of cell biology and physiology. More recently, their impact on cellular metabolism has been rediscovered. Our understanding of cell-type-specific GC actions and the crosstalk between various immune and stromal cells in arthritis models has evolved by investigating conditional GR mutant mice using the Cre/LoxP system. A major achievement in studying the complex, cell-type-specific interplay is the recent advent of omics technologies at single-cell resolution, which will provide further unprecedented insights into the cell types and factors mediating GC responses. Alongside gene-encoded factors, anti-inflammatory metabolites that participate in resolving inflammation by GCs during arthritis are just being uncovered. The translation of this knowledge into therapeutic concepts will help tackle inflammatory diseases and reduce side effects. In this review, we describe major milestones in preclinical research that led to our current understanding of GC and GR action 75 years after the first use of GCs in arthritis.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Impaired HPA-axis reactivity diminishes anti-inflammatory cortisol secretion and alters glucocorticoid receptor sensitivity, weakening feedback loops between the hypothalamus and pituitary.
“impaired HPA-axis reactivity diminishes anti-inflammatory cortisol secretion and alters glucocorticoid receptor sensitivity, weakening the feedback loops between the hypothalamus and pituitary [77,78]”
From Interorgan Communications in Skeletal Pathophysiology: From Molecular Pathways to Multidisciplinary Therapies (2026) · cites this paper as [77]
Cites
Weinstein, R. S., Jilka, R. L., Parfitt, A. M., & Manolagas, S. C. (1998) · Journal of Clinical Investigation · doi:10.1172/jci2799 · Cited by 1,753 · cited 1× · see citing works
“81 82 Conversely, GCs even can accelerate proliferation, for example, in the process of stress erythropoiesis.”
Yang-Yen, H.-F., Chambard, J.-C., Sun, Y.-L., Smeal, T., Schmidt, T. J., Drouin, J., & Karin, M. (1990) · Cell · doi:10.1016/0092-8674(90)90396-v · Cited by 1,553 · see citing works
Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA
Luisi, B. F., Xu, W. X., Otwinowski, Z., Freedman, L. P., Yamamoto, K. R., & Sigler, P. B. (1991) · Nature · doi:10.1038/352497a0 · Cited by 1,503 · see citing works
DNA binding of the glucocorticoid receptor is not essential for survival
Reichardt, H. M., Kaestner, K. H., Tuckermann, J., Kretz, O., Wessely, O., Bock, R., Gass, P., Schmid, W., Herrlich, P., Angel, P., et al. (1998) · Cell · doi:10.1016/s0092-8674(00)81183-6 · Cited by 1,068 · see citing works
Self-citationDistinct fibroblast subsets drive inflammation and damage in arthritis
Croft, A. P., Campos, J., Jansen, K., Turner, J. D., Marshall, J., Attar, M., Savary, L., Wehmeyer, C., Naylor, A. J., Kemble, S., et al. (2019) · Nature · doi:10.1038/s41586-019-1263-7 · Cited by 976 · see citing works
Joint profiling of chromatin accessibility and gene expression in thousands of single cells
Cao, J., Cusanovich, D. A., Ramani, V., Aghamirzaie, D., Pliner, H. A., Hill, A. J., Daza, R. M., McFaline-Figueroa, J. L., Packer, J. S., Christiansen, L., et al. (2018) · Science · doi:10.1126/science.aau0730 · Cited by 938 · see citing works
Annexin A1 and glucocorticoids as effectors of the resolution of inflammation
Perretti, M., & D'Acquisto, F. (2009) · Nature Reviews Immunology · doi:10.1038/nri2470 · Cited by 915 · see citing works
Abraham, S. M., Lawrence, T., Kleiman, A., Warden, P., Medghalchi, M., Tuckermann, J., Saklatvala, J., & Clark, A. R. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20060336 · Cited by 430 · see citing works
Wang, T., Liu, H., Lian, G., Zhang, S.-Y., Wang, X., & Jiang, C. (2017) · Mediators of Inflammation · doi:10.1155/2017/9029327 · Cited by 371 · see citing works
Lane, N. E., Yao, W., Balooch, M., Nalla, R. K., Balooch, G., Habelitz, S., Kinney, J. H., & Bonewald, L. F. (2006) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.051103 · Cited by 355 · see citing works
Crosstalk between the glucocorticoid receptor and other transcription factors: Molecular aspects
Kassel, O., & Herrlich, P. (2007) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2007.07.003 · Cited by 277 · see citing works
Uhlenhaut, N. H., Barish, G. D., Yu, R. T., Downes, M., Karunasiri, M., Liddle, C., Schwalie, P., Hübner, N., & Evans, R. M. (2013) · Molecular Cell · doi:10.1016/j.molcel.2012.10.013 · Cited by 265 · see citing works
Tuckermann, J. P., Kleiman, A., Moriggl, R., Spanbroek, R., Neumann, A., Illing, A., Clausen, B. E., Stride, B., Förster, I., Habenicht, A. J. R., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci28034 · Cited by 252 · see citing works
Tuckermann, J. P., Reichardt, H. M., Arribas, R., Richter, K. H., Schütz, G., & Angel, P. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.147.7.1365 · Cited by 196 · see citing works
Glucocorticoid dose determines osteocyte cell fate
Jia, J., Yao, W., Guan, M., Dai, W., Shahnazari, M., Kar, R., Bonewald, L., Jiang, J. X., & Lane, N. E. (2011) · The FASEB Journal · doi:10.1096/fj.11-182519 · Cited by 157 · see citing works
Kleiman, A., Hübner, S., Parkitna, J. M. R., Neumann, A., Hofer, S., Weigand, M. A., Bauer, M., Schmid, W., Schütz, G., Libert, C., et al. (2012) · The FASEB Journal · doi:10.1096/fj.11-192112 · Cited by 152 · see citing works
Silverman, M. N., Mukhopadhyay, P., Belyavskaya, E., Tonelli, L. H., Revenis, B. D., Doran, J. H., Ballard, B. E., Tam, J., Pacher, P., & Sternberg, E. M. (2013) · Molecular Psychiatry · doi:10.1038/mp.2012.131 · Cited by 64 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Gan, D., Qin, L., & Xiao, G. (2026) · Research · doi:10.34133/research.1319 · Cited by 1 · see citing works
“At the same time, impaired HPA-axis reactivity diminishes anti-inflammatory cortisol secretion and alters glucocorticoid receptor sensitivity, weakening the feedback loops between the hypothalamus and pituitary [ 77 , 78 ].”
- Authors
- Eiers, A.-K., Vettorazzi, S., & Tuckermann, J. P.
- Affiliations
- Universität Ulm (DE)
- Corresponding author
- Vettorazzi, Sabine
- Tuckermann, Jan P
- Venue
- Annals of the Rheumatic Diseases
- Publisher
- Elsevier BV
- Published
- 2024-12
- Volume
- 83
- Issue
- 12
- Pages
- 1603-1613
- ISSN
- 0003-4967 (ISSN-L)
- OpenAlex
- W4401406750
- Cited by
- 31
- References
- 17
- Citations by year
- 2026: 16 · 2025: 14 · 2024: 1
- FWCI
- 2.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Annals of the Rheumatic Diseases (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (TRR369 DIONE, Project Number Project Nr. 501752319)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- glucocorticoids, glucocorticoid receptor, rheumatic diseases, arthritis, autoimmune disease, cell type-specific gene expression, Cre-loxP system, single-cell omics, anti-inflammatory metabolites, inflammation resolution, glucocorticoid adverse effects
- MeSH terms
- Animals, Glucocorticoids, Humans, Receptors, Glucocorticoid, Rheumatic Diseases, History, 20th Century, History, 21st Century, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
