title: Pharmacological estrogen administration causes a FSH-independent osteo-anabolic effect requiring ER alpha in osteoblasts.
abstract: Postmenopausal osteoporosis is characterized by declining estrogen levels, and estrogen replacement therapy has been proven beneficial for preventing bone loss in affected women. While the physiological functions of estrogen in bone, primarily the inhibition of bone resorption, have been studied extensively, the effects of pharmacological estrogen administration are still poorly characterized. Since elevated levels of follicle-stimulating hormone (FSH) have been suggested to be involved in postmenopausal bone loss, we investigated whether the skeletal response to pharmacological estrogen administration is mediated in a FSH-dependent manner. Therefore, we treated wildtype and FSHβ-deficicent (Fshb(-/-)) mice with estrogen for 4 weeks and subsequently analyzed their skeletal phenotype. Here we observed that estrogen treatment resulted in a significant increase of trabecular and cortical bone mass in both, wildtype and Fshb(-/-) mice. Unexpectedly, this FSH-independent pharmacological effect of estrogen was not caused by influencing bone resorption, but primarily by increasing bone formation. To understand the cellular and molecular nature of this osteo-anabolic effect we next administered estrogen to mouse models carrying cell specific mutant alleles of the estrogen receptor alpha (ERα). Here we found that the response to pharmacological estrogen administration was not affected by ERα inactivation in osteoclasts, while it was blunted in mice lacking the ERα in osteoblasts or in mice carrying a mutant ERα incapable of DNA binding. Taken together, our findings reveal a previously unknown osteo-anabolic effect of pharmacological estrogen administration, which is independent of FSH and requires DNA-binding of ERα in osteoblasts.
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Seitz
authors.forename: Johannes
authors.initials: J
authors.lastname: Keller
authors.forename: Arndt F
authors.initials: AF
authors.lastname: Schilling
authors.forename: Anke
authors.initials: A
authors.lastname: Jeschke
authors.forename: Robert P
authors.initials: RP
authors.lastname: Marshall
authors.forename: Brenda D
authors.initials: BD
authors.lastname: Stride
authors.forename: Tim
authors.initials: T
authors.lastname: Wintermantel
authors.forename: Frank T
authors.initials: FT
authors.lastname: Beil
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
authors.forename: Jan
authors.initials: J
authors.lastname: Tuckermann
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
mesh_terms: D000483:Alleles; D000818:Animals; D001862:Bone Resorption; D003433:Crosses, Genetic; D004247:DNA / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D005786:Gene Expression Regulation; D005838:Genotype; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology; D011485:Protein Binding; D055114:X-Ray Microtomography
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D005640:Follicle Stimulating Hormone; D004247:DNA