The skeletal response to estrogen is impaired in female but not in male steroid receptor coactivator (SRC)-1 knock out mice

Bone. 2008 Feb;42(2):414-21. doi: 10.1016/j.bone.2007.10.017. Epub 2007 Nov 4.


Estrogen (E) is critical for the maintenance of bone mass in both female and male mice and steroid receptor coactivator (SRC)-1 has been shown to be important for mediating E effects on bone, at least in female mice. In the present study, we defined the skeletal phenotype of male SRC-1 knock out (KO) mice and compared it with their female littermates. Further, to determine the role of SRC-1 in mediating effects of E on bone in male mice, we examined the skeletal effects of gonadectomy (gnx) with or without E replacement in male mice and placed these findings in the context of our previous studies in female SRC-1 KO mice. Analysis of a large group of male (WT, n=67; SRC-1 KO, n=56) and female (WT, n=66; SRC-1 KO, n=70) mice showed a significant decrease in trabecular volumetric bone mineral density (vBMD) in SRC-1 KO mice compared to their WT littermates in both genders (male SRC-1 KO, 275+/-3 vs. WT, 295+/-3 mg/cm(3), P<0.001; female SRC-1 KO, 210+/-2 vs. WT, 221+/-2 mg/cm(3), P<0.001). Following gnx and E replacement (10 microg/kg/day), we previously demonstrated that SRC-1 KO female mice have a defect in E action in trabecular, but not in cortical bone. In contrast, we now demonstrate that the same dose of E administered to gnx'd male SRC-1 KO mice was sufficient to prevent trabecular bone loss in these mice. For example, in WT female mice, gnx followed by E replacement maintained spine BMD (1.2+/-3.4% vs. baseline) as compared to gnx without E replacement (-12.7+/-2.6%, P<0.001 vs. sham); this effect of E was absent in SRC-1 KO female mice. By contrast, the identical dose of E was equally effective in maintaining spine BMD in E-treated gnx'd male WT (-5.2+/-5.1% vs. baseline) and male SRC-1 KO (-5.4+/-5.3%) mice, respectively, as compared to gnx'd mice without E treatment (WT, -17.6+/-2.5%, P=0.02; SRC-1 KO, -28.6+/-2.6%, P<0.001 vs. sham). E treatment was effective in suppressing cancellous bone turnover in both gnx'd WT and SRC-1 KO male mice as determined by significant reductions in osteoblast and osteoclast numbers; however, in female mice, E treatment only suppressed bone turnover in WT but not in SRC-1 KO mice. Collectively, these findings demonstrate that loss of SRC-1 results in trabecular osteopenia in male and female mice, but in contrast to female mice, this is not due to any detectable resistance to E action in trabecular bone in male SRC-1 KO mice.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Body Weight / drug effects
  • Bone Density
  • Bone Diseases, Metabolic / genetics
  • Bone Diseases, Metabolic / metabolism
  • Bone Diseases, Metabolic / physiopathology
  • Bone and Bones / drug effects*
  • Bone and Bones / metabolism*
  • Estrogens / pharmacology*
  • Female
  • Histone Acetyltransferases / deficiency*
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Coactivator 1
  • Reproduction / drug effects
  • Sex Characteristics*
  • Transcription Factors / deficiency*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • Estrogens
  • Transcription Factors
  • Histone Acetyltransferases
  • Ncoa1 protein, mouse
  • Nuclear Receptor Coactivator 1