A mouse model of androgenetic alopecia.
Androgenetic alopecia (AGA), commonly known as male pattern baldness, is a form of hair loss that occurs in both males and females. Although the exact cause of AGA is not known, it is associated with genetic predisposition through traits related to androgen synthesis/metabolism and androgen signaling mediated by the androgen receptor (AR). Current therapies for AGA show limited efficacy and are often associated with undesirable side effects. A major hurdle to developing new therapies for AGA is the lack of small animal models to support drug discovery research. Here, we report the first rodent model of AGA. Previous work demonstrating that the interaction between androgen-bound AR and beta-catenin can inhibit Wnt signaling led us to test the hypothesis that expression of AR in hair follicle cells could interfere with hair growth in an androgen-dependent manner. Transgenic mice overexpressing human AR in the skin under control of the keratin 5 promoter were generated. Keratin 5-human AR transgenic mice exposed to high levels of 5alpha-dihydrotestosterone showed delayed hair regeneration, mimicking the AGA scalp. This effect is AR mediated, because treatment with the AR antagonist hydroxyflutamide inhibited the effect of dihydrotestosterone on hair growth. These results support the hypothesis that androgen-mediated hair loss is AR dependent and suggest that AR and beta-catenin mediate this effect. These mice can now be used to test new therapeutic agents for the treatment of AGA, accelerating the drug discovery process.
Department of Tissue Repair, Wyeth Research, Collegeville, Pennsylvania 19426, USA.
Judy S
JS
Crabtree
Edward J
EJ
Kilbourne
Bryan J
BJ
Peano
Susan
S
Chippari
Thomas
T
Kenney
Christopher
C
McNally
Wei
W
Wang
Heather A
HA
Harris
Richard C
RC
Winneker
Sunil
S
Nagpal
Catherine C
CC
Thompson
D000505:Alopecia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005485:Flutamide / Q000031:analogs & derivatives / Q000494:pharmacology; D006197:Hair / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D053555:Keratin-5 / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
C410798:AR protein, human; D000726:Androgen Antagonists; D000728:Androgens; D053555:Keratin-5; D011944:Receptors, Androgen; D051176:beta Catenin; D013196:Dihydrotestosterone; C014290:hydroxyflutamide; D005485:Flutamide