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Endocrine Research Unit (U.I.L.M., A.S., A.E.K., B.L.R., S.K.), Departments of Orthopedics (J.D.S.) and Biochemistry and Molecular Biology (T.C.S.), and Physiological Imaging Research Laboratory (E.L.S.), Department of Physiology and Biophysics, Mayo Clinic College of Medicine, Rochester, Minnesota 55905; and Department of Molecular and Cellular Biology (E.N., J.X., B.W.O.M.), Baylor College of Medicine, Houston, Texas 77030
Address all correspondence and requests for reprints to: Sundeep Khosla, M.D., Mayo Clinic, 200 First Street SW, 5-194 Joseph, Rochester, Minnesota 55905. E-mail: khosla.sundeep{at}mayo.edu.
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 (E2) dose of 10 µg/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 E2 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 E2 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.
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