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 R...

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Bibliographic Details
Published in:Endocrinology (Philadelphia) 1996-05, Vol.137 (5), p.2075-2084
Main Authors: Yang, N N, Bryant, H U, Hardikar, S, Sato, M, Galvin, R J, Glasebrook, A L, Termine, J D
Format: Article
Language:English
Subjects:
17β-Estradiol
Animal models
Animals
Bone density
Bone growth
Bone loss
Bone mineral density
Differentiation
Estrogen receptors
Estrogens
Femur
Gene expression
Growth factors
Maintenance
Nucleotide sequence
Osteoclastogenesis
Osteoclasts
Ovariectomy
Raloxifene
Reporter gene
Ribonucleic acid
RNA
Sex hormones
Transfection
Transforming growth factor-b
Transforming growth factor-b1
Vitellogenin
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Summary: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.
ISSN:0013-7227
1945-7170
DOI:10.1210/en.137.5.2075