Androgens stimulate erythropoiesis through the DNA-binding activity of the androgen receptor in non-hematopoietic cells.

Publisher: Blackwell Country of Publication: England NLM ID: 8703985 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1600-0609 (Electronic) Linking ISSN: 09024441 NLM ISO Abbreviation: Eur J Haematol Subsets: MEDLINE

Publication: <2005->: Oxford : Blackwell
Original Publication: Copenhagen : Munksgaard, c1987-

Erythropoiesis*/drug effects; Androgens/*metabolism ; DNA-Binding Proteins/*metabolism ; Receptors, Androgen/*metabolism; Androgens/pharmacology ; Animals ; Biomarkers ; Erythropoietin/blood ; Female ; Gene Expression Regulation ; Iron/metabolism ; Male ; Mice ; Mice, Transgenic ; Protein Binding ; Receptors, Androgen/genetics ; Signal Transduction

Background: Androgens function through DNA and non-DNA binding-dependent signalling of the androgen receptor (AR). How androgens promote erythropoiesis is not fully understood.
Design and Methods: To identify the androgen signalling pathway, we treated male mice lacking the second zinc finger of the DNA-binding domain of the AR (AR ^ΔZF2 ) with non-aromatizable 5α-dihydrotestosterone (5α-DHT) or aromatizable testosterone. To distinguish direct hematopoietic and non-hematopoietic mechanisms, we performed bone marrow reconstitution experiments.
Results: In wild-type mice, 5α-DHT had greater erythroid activity than testosterone, which can be aromatized to estradiol. The erythroid response in wild-type mice following 5α-DHT treatment was associated with increased serum erythropoietin (EPO) and its downstream target erythroferrone, and hepcidin suppression. 5α-DHT had no erythroid activity in AR ^ΔZF2 mice, proving the importance of DNA binding by the AR. Paradoxically, testosterone, but not 5α-DHT, suppressed EPO levels in AR ^ΔZF2 mice, suggesting testosterone following aromatization may oppose the erythroid-stimulating effects of androgens. Female wild-type mice reconstituted with AR ^ΔZF2 bone marrow cells remained responsive to 5α-DHT. In contrast, AR ^ΔZF2 mice reconstituted with female wild-type bone marrow cells showed no response to 5α-DHT.
Conclusion: Erythroid promoting effects of androgens are mediated through DNA binding-dependent actions of the AR in non-hematopoietic cells, including stimulating EPO expression.
(© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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National Health and Medical Research Council; Medical Research Future Fund; The Eva and Les Erdi Major Research Grants; Sir Edward Dunlop Medical Research Foundation Grants; The Austin Medical Research Fund; Leukaemia Foundation; Merck & Co.; Australian Cancer Research Foundation; The University of Melbourne MRGS

Keywords: DNA-binding actions; androgen receptor signalling; androgens; erythropoiesis; erythropoietin; genetically modified androgen receptor mouse model; non-hematopoietic cells

0 (Androgens)
0 (Biomarkers)
0 (DNA-Binding Proteins)
0 (EPO protein, human)
0 (Receptors, Androgen)
11096-26-7 (Erythropoietin)
E1UOL152H7 (Iron)

Date Created: 20200421 Date Completed: 20210616 Latest Revision: 20210616

20221213

10.1111/ejh.13431

32311143