Estrogen (Es) is essential to maintain normal bone balance in the adult skeleton.A deficiency of this hormone results in increased bone turnover and a net increase in bone resorption. The resulting osteopenia is an important contributing factor to the increased fracture risk in postmenopausal women. Es replacement therapy reduces the risk of osteoporosis in postmenopausal women by re-establishing normal bone turnover, but the potential health benefits of treatment must be weighted against an increased risk of life threatening side effects, including breast and uterine cancer. An exciting new approach to reduce the undesirable side effects of hormone replacement therapy is to substitute tissue-specific partial Es agonists for natural Es.The """"""""antiestrogen"""""""" tamoxifen (TAM) is an example of an Es analog that is primarily an Es agonist on the skeleton and liver under the same treatment conditions for which it is an antagonist on the uterus and breast. The mechanism for the mixed Es agonist/antagonist effects of TAM is unknown. Furthermore in spite of its important clinical manifestations, estrogen's mechanism of action on bone turnover is unclear. A goal of the proposed research is to characterize the effects of Es and selected partial Es agonists on bone cell dynamics in the ovariectomized rat model in order to reveal the cellular mechanism which mediates the bone loss following ovariectomy. The applicants will rely upon the application of dynamic bone histomorphometry, 3H-thymidine radioautography, Northern analysis of steady-state message levels for bone proteins, uptake and retention of radiolabeled compounds (3H- proline/14C-proline) into bone matrix, and serum and urine markers for bone metabolism. A second goal of the proposed research is to test the hypothesis that Es acts on bone target cells by inducing an Es receptor (ER)-mediated cascade. According to this model; Es regulates the expression of a relatively small number of critical genes whose expression (or repression) ultimately influences a much larger number of genes.They propose to test this cascade model for Es action in skeletal tissues of adult rats by investigating regulation of ER number and determining sequential changes in expression of putative early regulated genes (nuclear proto-oncogenes), middle genes (e.g. growth factors) and late genes (e.g., bone matrix protein). A further test of the cascade hypothesis will be performed by comparing the effects of mixed Es agonists/antagonists on early, middle and late genes in bone, liver and uterus. It is anticipated that the tissue-specific differences in the response to partial Es agonists result from chantes in the pattern of the hormone-induced cascade. These studies will rely upon Northern analysis and quantitative PCR. It is anticipated that the results of these studies will further clarify the mechanism of Es action on bone turnover and aid in the rational design of effective new approaches to hormone replacement therapy for osteoporosis.
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