PMID- 15312245
OWN - NLM
STAT- MEDLINE
DCOM- 20050223
LR  - 20161124
IS  - 0884-0431 (Print)
IS  - 0884-0431 (Linking)
VI  - 19
IP  - 9
DP  - 2004 Sep
TI  - SRC-1 is necessary for skeletal responses to sex hormones in both males and 
      females.
PG  - 1452-61
AB  - 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. 
      INTRODUCTION: 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. 
      MATERIALS AND 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. RESULTS AND 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.
FAU - Yamada, Takashi
AU  - Yamada T
AD  - Department of Orthopaedic Surgery, Faculty of Medicine, University of Tokyo, 
      Tokyo 113-8655, Japan.
FAU - Kawano, Hirotaka
AU  - Kawano H
FAU - Sekine, Keisuke
AU  - Sekine K
FAU - Matsumoto, Takahiro
AU  - Matsumoto T
FAU - Fukuda, Toru
AU  - Fukuda T
FAU - Azuma, Yoshiaki
AU  - Azuma Y
FAU - Itaka, Keiji
AU  - Itaka K
FAU - Chung, Ung-il
AU  - Chung UI
FAU - Chambon, Pierre
AU  - Chambon P
FAU - Nakamura, Kozo
AU  - Nakamura K
FAU - Kato, Shigeaki
AU  - Kato S
FAU - Kawaguchi, Hiroshi
AU  - Kawaguchi H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20040602
PL  - England
TA  - J Bone Miner Res
JT  - Journal of bone and mineral research : the official journal of the American 
      Society for Bone and Mineral Research
JID - 8610640
RN  - 0 (Gonadal Steroid Hormones)
RN  - 0 (Transcription Factors)
RN  - 0 (Viral Proteins)
RN  - EC 2.3.1.48 (Histone Acetyltransferases)
RN  - EC 2.3.1.48 (Ncoa1 protein, mouse)
RN  - EC 2.3.1.48 (Nuclear Receptor Coactivator 1)
RN  - EC 2.7.7.- (Cre recombinase)
RN  - EC 2.7.7.- (Integrases)
SB  - IM
MH  - Animals
MH  - Attachment Sites, Microbiological/genetics
MH  - Bone Diseases, Metabolic/metabolism/pathology
MH  - Female
MH  - Gene Deletion
MH  - Gonadal Steroid Hormones/administration & dosage/*pharmacology
MH  - Histone Acetyltransferases
MH  - Integrases/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Models, Animal
MH  - Musculoskeletal System/*drug effects
MH  - Nuclear Receptor Coactivator 1
MH  - Orchiectomy
MH  - Ovariectomy
MH  - Transcription Factors/deficiency/genetics/*metabolism
MH  - Viral Proteins/metabolism
EDAT- 2004/08/18 05:00
MHDA- 2005/02/24 09:00
CRDT- 2004/08/18 05:00
PHST- 2003/12/19 00:00 [received]
PHST- 2004/04/14 00:00 [revised]
PHST- 2004/05/07 00:00 [accepted]
PHST- 2004/08/18 05:00 [pubmed]
PHST- 2005/02/24 09:00 [medline]
PHST- 2004/08/18 05:00 [entrez]
AID - 10.1359/JBMR.040515 [doi]
PST - ppublish
SO  - J Bone Miner Res. 2004 Sep;19(9):1452-61. doi: 10.1359/JBMR.040515. Epub 2004 Jun 
      2.