Differential effects on bone of estrogen receptor alpha and androgen receptor activation in orchidectomized adult male mice.
Androgens may regulate the male skeleton either directly by stimulation of the androgen receptor (AR) or indirectly by aromatization of androgens into estrogens and, thereafter, by stimulation of the estrogen receptors (ERs). To directly compare the effect of ER activation on bone in vivo with the effect of AR activation, 9-month-old orchidectomized wild-type and ER-inactivated mice were treated with the nonaromatizable androgen 5alpha-dihydrotestosterone, 17beta-estradiol, or vehicle. Both ERalpha and AR but not ERbeta activation preserved the amount of trabecular bone. ERalpha activation resulted both in a preserved thickness and number of trabeculae. In contrast, AR activation exclusively preserved the number of trabeculae, whereas the thickness of the trabeculae was unaffected. Furthermore, the effects of 17beta-estradiol could not be mediated by the AR, and the effects of 5alpha-dihydrotestosterone were increased rather than decreased in ER-inactivated mice. ERalpha, but not AR or ERbeta, activation resulted in preserved thickness, volumetric density, and mechanical strength of the cortical bone. ERalpha activation increased serum levels of insulin-like growth factor I, which were positively correlated with all the cortical and trabecular bone parameters that were specifically preserved by ERalpha activation but not by AR activation, suggesting that insulin-like growth factor I might mediate these effects of ERalpha activation. Thus, the in vivo bone-sparing effect of ERalpha activation is distinct from the bone-sparing effect of AR activation in adult male mice. Because these two pathways are clearly distinct from each other, one may speculate that a combined treatment of selective ER modulators and selective AR modulators might be beneficial in the treatment of osteoporosis.
Movérare
Sofia
S
Center for Bone Research, Department of Internal Medicine, The Sahlgrenska Academy, Göteborg University, S-41345 Göteborg, Sweden.
Venken
Katrien
K
Eriksson
Anna-Lena
AL
Andersson
Niklas
N
Skrtic
Stanko
S
Wergedal
Jon
J
Mohan
Subburaman
S
Salmon
Phil
P
Bouillon
Roger
R
Gustafsson
Jan-Ake
JA
Vanderschueren
Dirk
D
Ohlsson
Claes
C
D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D005260:Female; D006579:Heterozygote; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis; D008297:Male; D051379:Mice; D015675:Osteocalcin / Q000097:blood; D010024:Osteoporosis / Q000378:metabolism; D011467:Prostate / Q000378:metabolism; D011944:Receptors, Androgen / Q000502:physiology*; D011960:Receptors, Estrogen / Q000502:physiology*; D013997:Time Factors; D014057:Tomography, X-Ray Computed
D047628:Estrogen Receptor alpha; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D013196:Dihydrotestosterone; D015675:Osteocalcin; D004958:Estradiol; D007334:Insulin-Like Growth Factor I