Pharmacological estrogen administration causes a FSH-independent osteo-anabolic effect requiring ER alpha in osteoblasts

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 -