ESTROGEN AND RALOXIFENE STIMULATE TRANSFORMING GROWTH FACTOR-BETA-3 GENE-EXPRESSION IN RAT BONE - A POTENTIAL MECHANISM FOR ESTROGEN-MEDIATED 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 associ ated with a 2-fold reduction of transforming growth factor-beta 3 (TGF beta 3) messenger RNA expression in the femur. Administration of 17 b eta-estradiol or raloxifene to ovariectomized rats restored both bone mineral density and TGF beta 3 messenger RNA expression in the femur t o 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 sufficien t to mediate 17 beta-estradiol or raloxifene induced-reporter gene exp ression 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 elem ent-containing vitellogenin promoter expression as a pure estrogen ant agonist. In two well characterized osteoclast differentiation models, TGF beta 3 significantly inhibited the differentiation and bone-resorp tive activities of murine and avian osteoclasts. These findings sugges t that regulation of TGF beta 3 gene expression by raloxifene or estro gen in bone may be an important target to mediate bone maintenance.