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Skeletal effects of estrogen are mediated by opposing actions of classical and nonclassical estrogen receptor

Farhan A Syed1, Ulrike I L Mödder, Daniel G Fraser

  • 1Endocrine Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.

Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research
|October 20, 2005
PubMed
Abstract

Insights

Estrogen receptor alpha (ER alpha) signaling in bone has two pathways: classical and nonclassical. Disrupting classical signaling in mice led to paradoxical responses to estrogen, highlighting the importance of balancing these pathways for bone health.

Area of Science:

  • Endocrinology
  • Bone Biology
  • Molecular Signaling

Background:

  • Estrogen receptor alpha (ER alpha) mediates its effects through classical estrogen response elements (EREs) or nonclassical pathways.
  • Understanding the distinct roles of these ER alpha signaling pathways in bone is crucial for bone health.
  • This study investigates the skeletal phenotype and estrogen response in mice with a mutated ER alpha incapable of ERE binding.

Purpose of the Study:

  • To define the skeletal phenotype of mice with impaired classical ER alpha signaling.
  • To investigate the response to ovariectomy and estrogen replacement in these genetically modified mice.
  • To elucidate the relative contributions of classical and nonclassical ER alpha pathways in bone regulation.

Main Methods:

  • Generation of mice with a mutation abolishing ERE binding (nonclassical ER alpha knock-in [NERKI]).
  • Phenotypic analysis of ER alpha(+/+), ER alpha(+/NERKI), and ER alpha(-/NERKI) female mice.
  • Assessment of bone mineral density (BMD) and responses to ovariectomy and estradiol treatment.

Main Results:

  • Mice lacking functional classical ER alpha signaling (ER alpha(-/NERKI)) exhibited cortical bone deficits.
  • Ovariectomy and estrogen replacement produced opposite effects on cortical bone in ER alpha(-/NERKI) mice compared to wild-type mice.
  • Estrogen demonstrated paradoxical effects on bone formation and resorption in the absence of classical ER alpha signaling.

Conclusions:

  • Altering the balance between classical and nonclassical ER alpha signaling pathways results in cortical bone deficits.
  • Complete loss of classical ER alpha signaling can lead to paradoxical responses to estrogen in bone.
  • A balance between classical and nonclassical ER alpha signaling is essential for normal estrogen response in bone.

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