Estrogen and raloxifene stimulate transforming growth factor-beta 3 gene expression in rat bone: a potential mechanism for estrogen- or raloxifene-mediated bone maintenance.
Estrogen or raloxifene (LY156758) prevent estrogen deficiency-induced bone loss in animals and humans. We demonstrated in the rat that a 22% reduction in bone mineral density generated by ovariectomy was associated with a 2-fold reduction of transforming growth factor-beta 3 (TGF beta 3) messenger RNA expression in the femur. Administration of 17 beta-estradiol or raloxifene to ovariectomized rats restored both bone mineral density and TGF beta 3 messenger RNA expression in the femur to levels measured in intact animals. In transient transfection assays, the promoter sequence from -38 to + 110 of the human TGF beta 3 gene, which contains no palindromic estrogen response element, was sufficient to mediate 17 beta-estradiol or raloxifene induced-reporter gene expression in presence of the estrogen receptor. Raloxifene activated TGF beta 3 promoter as a full agonist at nanomolar concentrations. In the same cellular system, raloxifene inhibited the estrogen response element-containing vitellogenin promoter expression as a pure estrogen antagonist. In two well characterized osteoclast differentiation models, TGF beta 3 significantly inhibited the differentiation and bone-resorptive activities of murine and avian osteoclasts. These findings suggest that regulation of TGF beta 3 gene expression by raloxifene or estrogen in bone may be an important target to mediate bone maintenance.
Yang
N N
NN
Endocrine Research, Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana 46285, USA.
Bryant
H U
HU
Hardikar
S
S
Sato
M
M
Galvin
R J
RJ
Glasebrook
A L
AL
Termine
J D
JD
D000818:Animals; D001483:Base Sequence; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D008969:Molecular Sequence Data; D010010:Osteoclasts / Q000166:cytology; D010052:Ovariectomy; D010880:Piperidines / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020849:Raloxifene Hydrochloride; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics*
D004965:Estrogen Antagonists; D010880:Piperidines; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D020849:Raloxifene Hydrochloride; D004958:Estradiol