Non-nuclear-initiated actions of the estrogen receptor protect cortical bone mass

Mol Endocrinol. 2013 Apr;27(4):649-56. doi: 10.1210/me.2012-1368. Epub 2013 Feb 26.


Extensive evidence has suggested that at least some of the effects of estrogens on bone are mediated via extranuclear estrogen receptor α signaling. However, definitive proof for this contention and the extent to which such effects may contribute to the overall protective effects of estrogens on bone maintenance have remained elusive. Here, we investigated the ability of a 17β-estradiol (E2) dendrimer conjugate (EDC), incapable of stimulating nuclear-initiated actions of estrogen receptor α, to prevent the effects of ovariectomy (OVX) on the murine skeleton. We report that EDC was as potent as an equimolar dose of E2 in preventing bone loss in the cortical compartment that represents 80% of the entire skeleton, but was ineffective on cancellous bone. In contrast, E2 was effective in both compartments. Consistent with its effect on cortical bone mass, EDC partially prevented the loss of both vertebral and femoral strength. In addition, EDC, as did E2, prevented the OVX-induced increase in osteoclastogenesis, osteoblastogenesis, and oxidative stress. Nonetheless, the OVX-induced decrease in uterine weight was unaltered by EDC but was restored by E2. These results demonstrate that the protection of cortical bone mass by estrogens is mediated, at least in part, via a mechanism that is distinct from the classic mechanism of estrogen action on reproductive organs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Atrophy
  • Bone Density / drug effects
  • Bone Remodeling / drug effects
  • Bone and Bones / drug effects
  • Bone and Bones / metabolism*
  • Bone and Bones / pathology*
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism*
  • Estradiol / pharmacology
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Femur / drug effects
  • Femur / pathology
  • Femur / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Organ Size / drug effects
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism
  • Osteoclasts / pathology
  • Osteogenesis / drug effects
  • Ovariectomy
  • Oxidative Stress / drug effects
  • Spine / drug effects
  • Spine / pathology
  • Spine / physiopathology
  • Uterus / drug effects
  • Uterus / pathology


  • Estrogen Receptor alpha
  • Estradiol