SRC-1 is necessary for skeletal responses to sex hormones in both males and females.
We created SRC-1(-/-) mice by mating floxed SRC-1 mice with CMV-Cre transgenic mice. The SRC-1(-/-) mice showed high turnover osteopenia under physiological conditions and hardly responded to osteoanabolic actions of exogenous androgen and estrogen in males and females, respectively, after gonadectomies, indicating that SRC-1 is essential for the maintenance of bone mass by sex hormones.


BACKGROUND
Steroid receptor coactivator-1 (SRC-1) is the first identified coactivator of nuclear receptors. This study investigated the role of SRC-1 in skeletal tissues of males and females using the deficient (SRC-1(-/-)) mice.


METHODS
SRC-1(-/-) mice were generated by mating our original floxed SRC-1 mice with CMV-Cre transgenic mice. Bone metabolism between 24-week-old SRC-1(-/-) and wildtype (WT) littermates under physiological conditions was compared in males and females by radiological, histological, and biochemical analyses. Difference of skeletal responses to steroid hormones was examined by gonadectomies and exogenous administration experiments with the hormones. Statistical analysis was performed by ANOVA determined by posthoc testing using Bonferroni's method.


CONCLUSIONS
Although SRC-1(-/-) mice showed no abnormality in growth or major organs, both males and females showed osteopenia with high bone turnover in the trabecular bones, but not in the cortical bones, compared with WT littermates. Their serum levels of sex hormones were upregulated, suggesting a compensatory reaction for the insensitivity to these hormones. Gonadectomies caused decreases in BMDs of SRC-1(-/-) and WT mice to the same levels; however, replacement with 5 alpha-dihydrotestosterone and 17 beta-estradiol in males and females, respectively, failed to restore the bone loss in SRC-1(-/-), whereas the WT bone volume was increased to the sham-operated levels. In contrast, bone loss by administered prednisolone was similarly seen in SRC-1(-/-) and WT mice. We conclude that SRC-1 is essential for the maintenance of bone mass by sex hormones, but not for the catabolic action of glucocorticoid, under both physiological and pathological conditions.
Department of Orthopaedic Surgery, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Takashi
T
Yamada
Hirotaka
H
Kawano
Keisuke
K
Sekine
Takahiro
T
Matsumoto
Toru
T
Fukuda
Yoshiaki
Y
Azuma
Keiji
K
Itaka
Ung-il
UI
Chung
Pierre
P
Chambon
Kozo
K
Nakamura
Shigeaki
S
Kato
Hiroshi
H
Kawaguchi
D000818:Animals; D001287:Attachment Sites, Microbiological / Q000235:genetics; D001851:Bone Diseases, Metabolic / Q000378:metabolism / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D012739:Gonadal Steroid Hormones / Q000008:administration & dosage / Q000494:pharmacology*; D051548:Histone Acetyltransferases; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D009141:Musculoskeletal System / Q000187:drug effects*; D056920:Nuclear Receptor Coactivator 1; D009919:Orchiectomy; D010052:Ovariectomy; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism
D012739:Gonadal Steroid Hormones; D014157:Transcription Factors; D014764:Viral Proteins; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1; C045073:Cre recombinase; D019426:Integrases