title: Effects of loss of steroid receptor coactivator-1 on the skeletal response to estrogen in mice.
abstract: Steroid receptor coactivator (SRC)-1 is an important nuclear receptor coactivator that enhances estrogen (E) action in many tissues, but its role in mediating E effects on bone is unknown. Thus, we assessed the skeletal response to ovariectomy (ovx) and E replacement in SRC-1 knockout (KO) mice compared with wild-type (WT) littermates. Bone mineral density was measured by dual-energy x-ray absorptiometry and peripheral quantitative computed tomography at baseline and after 2 months of sham surgery, ovx, or ovx plus E replacement. Microcomputed tomography and bone histomorphometry were also performed at the end of the study. Both WT and SRC-1 KO mice lost bone at multiple sites after ovx; however, although an estradiol (E(2)) dose of 10 microg/kg.d completely prevented loss of cancellous bone (at the lumbar spine and tibial metaphysis) in the WT mice, it was entirely ineffective in preventing cancellous bone loss at these sites in the SRC-1 KO mice. This E(2) dose was, however, equally effective on cortical bone in the tibia in the SRC-1 KO and WT mice. Moreover, a 4-fold higher dose of E(2) was able to overcome the deficit in E action in cancellous bone in the SRC-1 KO mice. These findings establish that, in mice, loss of SRC-1 leads to skeletal resistance to E predominantly in cancellous bone.
authors.affiliation: Mayo Clinic, 200 First Street SW, 5-194 Joseph, Rochester, MN 55905, USA.
authors.forename: Ulrike I L
authors.initials: UI
authors.lastname: Mödder
authors.forename: Arunik
authors.initials: A
authors.lastname: Sanyal
authors.forename: Ann E
authors.initials: AE
authors.lastname: Kearns
authors.forename: Jean D
authors.initials: JD
authors.lastname: Sibonga
authors.forename: Eijun
authors.initials: E
authors.lastname: Nishihara
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.forename: Erik L
authors.initials: EL
authors.lastname: Ritman
authors.forename: B Lawrence
authors.initials: BL
authors.lastname: Riggs
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Spelsberg
authors.forename: Sundeep
authors.initials: S
authors.lastname: Khosla
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D015519:Bone Density; D001842:Bone and Bones / Q000737:chemistry; D004958:Estradiol / Q000008:administration & dosage*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D015914:Estrogen Replacement Therapy; D005260:Female; D015870:Gene Expression; D051548:Histone Acetyltransferases; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D009929:Organ Size / Q000187:drug effects; D010024:Osteoporosis / Q000209:etiology / Q000517:prevention & control; D010052:Ovariectomy; D012333:RNA, Messenger / Q000032:analysis; D011960:Receptors, Estrogen / Q000235:genetics; D014057:Tomography, X-Ray Computed; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014599:Uterus / Q000033:anatomy & histology
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D051958:Nuclear Receptor Coactivator 2; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D014157:Transcription Factors; D004958:Estradiol; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1