Estrogen and Raloxifene Stimulate Transforming Growth Factor-β3 Gene Expression in Rat Bone: A Potential Mechanism for Estrogen- or Raloxifene-Mediated Bone Maintenance

Abstract

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-β3 (TGFβ3) messenger RNA expression in the femur. Administration of 17β-estradiol or raloxifene to ovariectomized rats restored both bone mineral density and TGFβ3 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 TGFβ3 gene, which contains no palindromic estrogen response element, was sufficient to mediate 17β-estradiol or raloxifene induced- reporter gene expression in presence of the estrogen receptor. Raloxifene activated TGFβ3 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, TGFβ3 significantly inhibited the differentiation and bone-resorptive activities of murine and avian osteoclasts. These findings suggest that regulation of TGFβ3 gene expression by raloxifene or estrogen in bone may be an important target to mediate bone maintenance.