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Androgens stimulate erythropoiesis through the DNA‐binding activity of the androgen receptor in non‐hematopoietic cells
Author(s) -
McManus Julie F.,
Nguyen NhuY N.,
Davey Rachel A.,
MacLean Helen E.,
Pomilio Giovanna,
McCormack Matthew P.,
Chiu Wan Sze,
Wei Andrew H.,
Zajac Jeffrey D.,
Curtis David J.
Publication year - 2020
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/ejh.13431
Subject(s) - medicine , testosterone (patch) , androgen receptor , endocrinology , dihydrotestosterone , haematopoiesis , erythropoiesis , erythropoietin , androgen , biology , bone marrow , receptor , chemistry , hormone , microbiology and biotechnology , stem cell , anemia , prostate cancer , cancer
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.