title: Functional adaptation in female rats: the role of estrogen signaling.
abstract: BACKGROUND
  Sex steroids have direct effects on the skeleton. Estrogen acts on the skeleton via the classical genomic estrogen receptors alpha and beta (ERα and ERβ), a membrane ER, and the non-genomic G-protein coupled estrogen receptor (GPER). GPER is distributed throughout the nervous system, but little is known about its effects on bone. In male rats, adaptation to loading is neuronally regulated, but this has not been studied in females.
  
  
  RESULTS
  We used the rat ulna end-loading model to induce an adaptive modeling response in ovariectomized (OVX) female Sprague-Dawley rats. Rats were treated with a placebo, estrogen (17β-estradiol), or G-1, a GPER-specific agonist. Fourteen days after OVX, rats underwent unilateral cyclic loading of the right ulna; half of the rats in each group had brachial plexus anesthesia (BPA) of the loaded limb before loading. Ten days after loading, serum estrogen concentrations, dorsal root ganglion (DRG) gene expression of ERα, ERβ, GPER, CGRPα, TRPV1, TRPV4 and TRPA1, and load-induced skeletal responses were quantified. We hypothesized that estrogen and G-1 treatment would influence skeletal responses to cyclic loading through a neuronal mechanism. We found that estrogen suppresses periosteal bone formation in female rats. This physiological effect is not GPER-mediated. We also found that absolute mechanosensitivity in female rats was decreased, when compared with male rats. Blocking of adaptive bone formation by BPA in Placebo OVX females was reduced.
  
  
  CONCLUSIONS
  Estrogen acts to decrease periosteal bone formation in female rats in vivo. This effect is not GPER-mediated. Gender differences in absolute bone mechanosensitivity exist in young Sprague-Dawley rats with reduced mechanosensitivity in females, although underlying bone formation rate associated with growth likely influences this observation. In contrast to female and male rats, central neuronal signals had a diminished effect on adaptive bone formation in estrogen-deficient female rats.
authors.affiliation: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Susannah J
authors.initials: SJ
authors.lastname: Sample
authors.forename: Molly A
authors.initials: MA
authors.lastname: Racette
authors.forename: Zhengling
authors.initials: Z
authors.lastname: Hao
authors.forename: Cathy F
authors.initials: CF
authors.lastname: Thomas
authors.forename: Mary
authors.initials: M
authors.lastname: Behan
authors.forename: Peter
authors.initials: P
authors.lastname: Muir
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D000758:Anesthesia; D000818:Animals; D001917:Brachial Plexus / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D010012:Osteogenesis / Q000187:drug effects; D010052:Ovariectomy; D010521:Periosteum / Q000187:drug effects / Q000254:growth & development; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects; D050916:TRPV Cation Channels / Q000378:metabolism; D014457:Ulna / Q000187:drug effects / Q000254:growth & development; D016474:Weight-Bearing
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D043562:Receptors, G-Protein-Coupled; D050916:TRPV Cation Channels