Pharmacological estrogen administration causes a FSH-independent osteo-anabolic effect requiring ER alpha in osteoblasts
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Pharmacological estrogen administration causes a FSH-independent osteo-anabolic effect requiring ER alpha in osteoblasts. / Seitz, Sebastian; Keller, Johannes; Schilling, Arndt F; Jeschke, Anke; Marshall, Robert P; Stride, Brenda D; Wintermantel, Tim; Beil, Frank T; Amling, Michael; Schütz, Günther; Tuckermann, Jan; Schinke, Thorsten.
in: PLOS ONE, Jahrgang 7, Nr. 11, 01.01.2012, S. e50301.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Pharmacological estrogen administration causes a FSH-independent osteo-anabolic effect requiring ER alpha in osteoblasts
AU - Seitz, Sebastian
AU - Keller, Johannes
AU - Schilling, Arndt F
AU - Jeschke, Anke
AU - Marshall, Robert P
AU - Stride, Brenda D
AU - Wintermantel, Tim
AU - Beil, Frank T
AU - Amling, Michael
AU - Schütz, Günther
AU - Tuckermann, Jan
AU - Schinke, Thorsten
PY - 2012/1/1
Y1 - 2012/1/1
N2 - 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.
AB - 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.
KW - Alleles
KW - Animals
KW - Bone Resorption
KW - Crosses, Genetic
KW - DNA
KW - Estrogen Receptor alpha
KW - Estrogens
KW - Female
KW - Follicle Stimulating Hormone
KW - Gene Expression Regulation
KW - Genotype
KW - Mice
KW - Mice, Transgenic
KW - Mutation
KW - Osteoblasts
KW - Osteoclasts
KW - Protein Binding
KW - X-Ray Microtomography
U2 - 10.1371/journal.pone.0050301
DO - 10.1371/journal.pone.0050301
M3 - SCORING: Journal article
C2 - 23209701
VL - 7
SP - e50301
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 11
ER -