Molecular Mechanisms of Glucocorticoids on Skeleton and Bone Regeneration After Fracture

Overview

Journal J Mol Endocrinol

Specialties Endocrinology
Molecular Biology

Date 2018 Mar 29

PMID 29588427

Citations 38

Authors

Yasmine Hachemi

Anna E Rapp

Ann-Kristin Picke

Gilbert Weidinger

Anita Ignatius

Jan Tuckermann

Affiliations

Soon will be listed here.

Abstract

Glucocorticoid hormones (GCs) have profound effects on bone metabolism. Via their nuclear hormone receptor - the GR - they act locally within bone cells and modulate their proliferation, differentiation, and cell death. Consequently, high glucocorticoid levels - as present during steroid therapy or stress - impair bone growth and integrity, leading to retarded growth and glucocorticoid-induced osteoporosis, respectively. Because of their profound impact on the immune system and bone cell differentiation, GCs also affect bone regeneration and fracture healing. The use of conditional-mutant mouse strains in recent research provided insights into the cell-type-specific actions of the GR. However, despite recent advances in system biology approaches addressing GR genomics in general, little is still known about the molecular mechanisms of GCs and GR in bone cells. Here, we review the most recent findings on the molecular mechanisms of the GR in general and the known cell-type-specific actions of the GR in mesenchymal cells and their derivatives as well as in osteoclasts during bone homeostasis, GC excess, bone regeneration and fracture healing.

Citing Articles

Foliar spraying with zinc oxide nanoparticles enhances the anti-osteoporotic efficacy of the fruit extracts of L. by stimulating silybin production.

Fahad Almulhim B, Sherif F, Younis N, Safwat Y, Khattab S Front Plant Sci. 2025; 15():1421485.

PMID: 39840357 PMC: 11747799. DOI: 10.3389/fpls.2024.1421485.

Synthesis and Anti-Cancer Activity of the Novel Selective Glucocorticoid Receptor Agonists of the Phenylethanolamine Series.

Zhidkova E, Tilova L, Fetisov T, Kirsanov K, Kulikov E, Enikeev A Int J Mol Sci. 2024; 25(16).

PMID: 39201590 PMC: 11354514. DOI: 10.3390/ijms25168904.

Plasminogen activator inhibitor-1 is involved in glucocorticoid-induced decreases in angiogenesis during bone repair in mice.

Okada K, Niwa Y, Fukuhara K, Ohira T, Mizukami Y, Kawao N J Bone Miner Metab. 2024; 42(3):282-289.

PMID: 38704516 DOI: 10.1007/s00774-024-01510-w.

Effects of restraint stress and surface treatments on the stability of titanium dental implant osseointegration in dogs: An in vivo comparative study.

Abdulla M, Hasan R, Al-Hyani O J Taibah Univ Med Sci. 2024; 19(3):461-472.

PMID: 38544871 PMC: 10965825. DOI: 10.1016/j.jtumed.2024.03.004.

The Therapeutic Potential of Two Egyptian Plant Extracts for Mitigating Dexamethasone-Induced Osteoporosis in Rats: Nrf2/HO-1 and RANK/RANKL/OPG Signals.

Saleh S, Saleh O, El-Bessoumy A, Sheta E, Ghareeb D, Eweda S Antioxidants (Basel). 2024; 13(1).

PMID: 38247490 PMC: 10812806. DOI: 10.3390/antiox13010066.

References

Caplan A . Mesenchymal stem cells. J Orthop Res. 1991; 9(5):641-50. DOI: 10.1002/jor.1100090504. View

Lim H, Uhlenhaut N, Rauch A, Weiner J, Hubner S, Hubner N . Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo. Genome Res. 2015; 25(6):836-44. PMC: 4448680. DOI: 10.1101/gr.188581.114. View

Rauner M, Goettsch C, Stein N, Thiele S, Bornhaeuser M, De Bosscher K . Dissociation of osteogenic and immunological effects by the selective glucocorticoid receptor agonist, compound A, in human bone marrow stromal cells. Endocrinology. 2010; 152(1):103-12. DOI: 10.1210/en.2010-0456. View

Rauch A, Gossye V, Bracke D, Gevaert E, Jacques P, Van Beneden K . An anti-inflammatory selective glucocorticoid receptor modulator preserves osteoblast differentiation. FASEB J. 2011; 25(4):1323-32. DOI: 10.1096/fj.10-173393. View

De Bosscher K, Beck I, Dejager L, Bougarne N, Gaigneaux A, Chateauvieux S . Selective modulation of the glucocorticoid receptor can distinguish between transrepression of NF-κB and AP-1. Cell Mol Life Sci. 2013; 71(1):143-63. PMC: 3889831. DOI: 10.1007/s00018-013-1367-4. View

Heinrichs C, Yanovski J, Roth A, Yu Y, Domene H, Yano K . Dexamethasone increases growth hormone receptor messenger ribonucleic acid levels in liver and growth plate. Endocrinology. 1994; 135(3):1113-8. DOI: 10.1210/endo.135.3.8070354. View

Baschant U, Tuckermann J . The role of the glucocorticoid receptor in inflammation and immunity. J Steroid Biochem Mol Biol. 2010; 120(2-3):69-75. DOI: 10.1016/j.jsbmb.2010.03.058. View

Conaway H, Henning P, Lie A, Tuckermann J, Lerner U . Activation of dimeric glucocorticoid receptors in osteoclast progenitors potentiates RANKL induced mature osteoclast bone resorbing activity. Bone. 2016; 93:43-54. DOI: 10.1016/j.bone.2016.08.024. View

Weinstein R, Wan C, Liu Q, Wang Y, Almeida M, OBrien C . Endogenous glucocorticoids decrease skeletal angiogenesis, vascularity, hydration, and strength in aged mice. Aging Cell. 2010; 9(2):147-61. PMC: 2858771. DOI: 10.1111/j.1474-9726.2009.00545.x. View

10.

Henriksen K, Karsdal M, Martin T . Osteoclast-derived coupling factors in bone remodeling. Calcif Tissue Int. 2013; 94(1):88-97. DOI: 10.1007/s00223-013-9741-7. View

11.

Park D, Spencer J, Koh B, Kobayashi T, Fujisaki J, Clemens T . Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration. Cell Stem Cell. 2012; 10(3):259-72. PMC: 3652251. DOI: 10.1016/j.stem.2012.02.003. View

12.

Weikum E, Knuesel M, Ortlund E, Yamamoto K . Glucocorticoid receptor control of transcription: precision and plasticity via allostery. Nat Rev Mol Cell Biol. 2017; 18(3):159-174. PMC: 6257982. DOI: 10.1038/nrm.2016.152. View

13.

Sehring I, Jahn C, Weidinger G . Zebrafish fin and heart: what's special about regeneration?. Curr Opin Genet Dev. 2016; 40:48-56. DOI: 10.1016/j.gde.2016.05.011. View

14.

Sundahl N, Bridelance J, Libert C, De Bosscher K, Beck I . Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds. Pharmacol Ther. 2015; 152:28-41. DOI: 10.1016/j.pharmthera.2015.05.001. View

15.

Komori T . Glucocorticoid Signaling and Bone Biology. Horm Metab Res. 2016; 48(11):755-763. DOI: 10.1055/s-0042-110571. View

16.

Conradie M, Cato A, Ferris W, de Wet H, Horsch K, Hough S . MKP-1 knockout does not prevent glucocorticoid-induced bone disease in mice. Calcif Tissue Int. 2011; 89(3):221-7. DOI: 10.1007/s00223-011-9509-x. View

17.

Weber A, Li G, Kalak R, Street J, Buttgereit F, Dunstan C . Osteoblast-targeted disruption of glucocorticoid signalling does not delay intramembranous bone healing. Steroids. 2010; 75(3):282-6. DOI: 10.1016/j.steroids.2010.01.005. View

18.

Stahn C, Buttgereit F . Genomic and nongenomic effects of glucocorticoids. Nat Clin Pract Rheumatol. 2008; 4(10):525-33. DOI: 10.1038/ncprheum0898. View

19.

van Staa T, Leufkens H, Abenhaim L, Zhang B, Cooper C . Use of oral corticosteroids and risk of fractures. J Bone Miner Res. 2000; 15(6):993-1000. DOI: 10.1359/jbmr.2000.15.6.993. View

20.

De Vrieze E, van Kessel M, PETERS H, Spanings F, Flik G, Metz J . Prednisolone induces osteoporosis-like phenotype in regenerating zebrafish scales. Osteoporos Int. 2013; 25(2):567-78. DOI: 10.1007/s00198-013-2441-3. View