Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts.
Estrogen prevents osteoporotic bone loss by attenuating bone resorption; however, the molecular basis for this is unknown. Here, we report a critical role for the osteoclastic estrogen receptor alpha (ERalpha) in mediating estrogen-dependent bone maintenance in female mice. We selectively ablated ERalpha in differentiated osteoclasts (ERalpha(DeltaOc/DeltaOc)) and found that ERalpha(DeltaOc/DeltaOc) females, but not males, exhibited trabecular bone loss, similar to the osteoporotic bone phenotype in postmenopausal women. Further, we show that estrogen induced apoptosis and upregulation of Fas ligand (FasL) expression in osteoclasts of the trabecular bones of WT but not ERalpha(DeltaOc/DeltaOc) mice. The expression of ERalpha was also required for the induction of apoptosis by tamoxifen and estrogen in cultured osteoclasts. Our results support a model in which estrogen regulates the life span of mature osteoclasts via the induction of the Fas/FasL system, thereby providing an explanation for the osteoprotective function of estrogen as well as SERMs.
Nakamura
Takashi
T
Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-0032, Japan.
Imai
Yuuki
Y
Matsumoto
Takahiro
T
Sato
Shingo
S
Takeuchi
Kazusane
K
Igarashi
Katsuhide
K
Harada
Yoshifumi
Y
Azuma
Yoshiaki
Y
Krust
Andree
A
Yamamoto
Yoko
Y
Nishina
Hiroshi
H
Takeda
Shu
S
Takayanagi
Hiroshi
H
Metzger
Daniel
D
Kanno
Jun
J
Takaoka
Kunio
K
Martin
T John
TJ
Chambon
Pierre
P
Kato
Shigeaki
S
D000818:Animals; D017209:Apoptosis; D015519:Bone Density; D001851:Bone Diseases, Metabolic / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D016723:Bone Remodeling / Q000187:drug effects; D056657:Cathepsin K; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D005260:Female; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010052:Ovariectomy; D010641:Phenotype; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D019014:fas Receptor / Q000378:metabolism*